Polypeptides

ABSTRACT

The invention relates to polypeptides comprising an amino acid sequence which is an analogue of human amylin, pharmaceutical compositions comprising these polypeptides, and these polypeptides for use as medicaments.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/930,075, filed Jun. 28, 2013, which is a continuation ofInternational Application No. PCT/EP2013/058165, filed Apr. 19, 2013,which claimed priority of European Patent Application 12164692.1, filedApr. 19, 2012; this application also claims priority under 35 U.S.C.§119(e) of U.S. Provisional application 61/637,806, filed Apr. 24, 2012;the contents of all above-named applications are incorporated herein byreference.

FIELD OF THE INVENTION

The invention relates to polypeptides comprising an amino acid sequencewhich is an analogue of SEQ ID No: 1 (human amylin), pharmaceuticalcompositions comprising these polypeptides, and these polypeptides foruse as medicaments.

BACKGROUND OF THE INVENTION

A large and growing number of people suffer from diabetes mellitus andobesity. Diabetes mellitus is a metabolic disorder in which the abilityto utilize glucose is partly or completely lost.

A number of treatment regimes target excessive blood glucose whereasothers are focused primarily on weight reduction. The most efficientanti-diabetic agent used to lower blood glucose is insulin andanalogue(s) thereof. It has been known for a long time that whentraditional insulin is used to treat diabetes, it is associated with anincrease in body weight. Insulin has to be injected subcutaneously up toseveral times per day.

Type 2 diabetes is generally treated in the early phases with diet andexercise. As the condition progresses, various oral anti-diabetic agentsare added. Injected agents such as GLP-1 analogues may also be used atthis stage. In general, these agents are most efficient in patients withfunctioning beta-cells capable of releasing insulin and amylin.

Human amylin is a 37 amino acid long polypeptide which hasphysico-chemical properties that make its use as a drug troublesome. Inparticular, it has a tendency for fibrillogenesis, i.e. the formation offibrils, in vitro and/or ex vivo and becomes ineffective due toprecipitation. Additionally amylin is difficult to formulate as it ischemically unstable and it precipitates at physiologic pH. Therefore itis formulated in acidic solution.

Human amylin binds to two distinct receptor complexes. These twocomplexes contain the calcitonin receptor plus a receptoractivity-modifying proteins, RAMP1 or RAMP3. From the close relationshipbetween the calcitonin receptor and the amylin receptor somecross-reactivity to the calcitonin receptor may be expected of amylinreceptor agonist. As an example pramlintide has some affinity to thecalcitonin receptor but is 14 times more potent on the amylin receptor.

Pramlintide is a drug product marketed by Amylin Pharmaceuticals asSymlin® for the treatment of diabetes as an add-on to insulin.Pramlintide is an amylin receptor agonist. It is approximately 14 timesless active on the calcitonin receptor.

The chemical structure of pramlintide is presented below and also inFIG. 5.

Pramlintide is chemically unstable at neutral pH and it is thereforeprovided in an acidic solution. Compared to human amylin, the aminoacids in position 25, 28 and 29 in pramlintide are substituted withproline. This modification reduces the tendency of the protein forfibrillogenesis. Parmlintide has a very short plasma half-life andtherefore has to be injected two to three times daily

WO 2010/046357 discloses polypeptides comprising human amylin analogues(having an albumin binding moiety. WO 2009/034119 also disclosespolypeptides comprising human amylin analogues having an albumin bindingmoiety. Even though these polypeptides with albumin binding moietiesshow improved pharmacokinetic (PK) or pharmacodynamic (PD) propertiescompared to pramlintide, they may still show poor physical stabilityunder certain conditions. In addition, the polypeptides generally do notshow selectivity for the amylin receptor over the calcitonin receptor.

The calcitonin receptor is found in many tissues throughout the body andit is believed to be involved in regulation of bone metabolism. However,apart from bone regulation, very little is known about the physiology ofcalcitonin receptors in humans. It is therefore believed that amylinbased polypeptides that have an increased selectivity for the amylinreceptor compared to calcitonin activity could offer an advantageouspharmacokinetic and pharmacological profile.

SUMMARY OF THE INVENTION

It has been surprisingly found that polypeptides comprising an aminoacid which is an analogue of SEQ ID No: 1 (human amylin) wherein theamino acid residue at position 21 is proline can demonstrate increasedselectivity for the amylin receptor over the calcitonin receptor.

At least in some embodiments the polypeptides of the present inventionhave an increased selectivity for the amylin receptor compared tocalcitonin activity.

At least in some embodiments the polypeptides of the present inventiondisplay an advantageous pharmacokinetic profile and/or advantageouspharmacological profile. An example of an advantageous pharmacokineticprofile is a long acting profile.

In one broad embodiment, the present invention relates to a polypeptidecomprising an amino acid sequence which is an analogue of SEQ ID No: 1wherein said analogue comprises a proline residue at position 21,wherein the amino acid sequence numbering of the analogue corresponds tothe amino acid numbering sequence of SEQ ID No: 1. Optionally, thepolypeptide has an IC₅₀ in a human amylin receptor binding assay (suchas that disclosed herein) of about 1200 pM or less. Optionally thepolypeptide has at least one substituent attached to at least one of itsamino acid residues. The present invention also relates topharmaceutical formulations comprising same. The present invention alsorelates to pharmaceutical uses of same. The present invention alsorelates to the delivery (such as administration) of same to patients inneed of treatment of same.

In another broad embodiment, the present invention relates to apolypeptide comprising an amino acid sequence which is an analogue ofSEQ ID No: 1 wherein said analogue comprises a proline residue atposition 21 and a proline residue at position 27, wherein the amino acidsequence numbering of the analogue corresponds to the amino acidnumbering sequence of SEQ ID No: 1. Optionally, the polypeptide has anIC₅₀ in a human amylin receptor binding assay (such as that disclosedherein) of about 1200 pM or less. Optionally the polypeptide has atleast one substituent attached to at least one of its amino acidresidues. The present invention also relates to pharmaceuticalformulations comprising same. The present invention also relates topharmaceutical uses of same. The present invention also relates to thedelivery (such as administration) of same to patients in need oftreatment of same.

In another broad embodiment, the present invention relates to apolypeptide comprising an amino acid sequence which is an analogue ofSEQ ID No: 1 wherein said analogue comprises a proline residue atposition 21, a proline residue at position 27 and an arginine residue atposition 17, wherein the amino acid sequence numbering of the analoguecorresponds to the amino acid numbering sequence of SEQ ID No: 1.Optionally, the polypeptide has an IC₅₀ in a human amylin receptorbinding assay (such as that disclosed herein) of about 1200 pM or less.Optionally the polypeptide has at least one substituent attached to atleast one of its amino acid residues. The present invention also relatesto pharmaceutical formulations comprising same. The present inventionalso relates to pharmaceutical uses of same. The present invention alsorelates to the delivery (such as administration) of same to patients inneed of treatment of same.

In another broad embodiment, the present invention relates to apolypeptide comprising an amino acid sequence which is an analogue ofSEQ ID No: 1 wherein said analogue comprises a proline residue atposition 21, a proline residue at position 27, an arginine residue atposition 17 and an aspartic acid residue at position 14, wherein theamino acid sequence numbering of the analogue corresponds to the aminoacid numbering sequence of SEQ ID No: 1. Optionally, the polypeptide hasan IC₅₀ in a human amylin receptor binding assay (such as that disclosedherein) of about 1200 pM or less. Optionally the polypeptide has atleast one substituent attached to at least one of its amino acidresidues. The present invention also relates to pharmaceuticalformulations comprising same. The present invention also relates topharmaceutical uses of same. The present invention also relates to thedelivery (such as administration) of same to patients in need oftreatment of same.

In another broad embodiment, the present invention relates to apolypeptide comprising an amino acid sequence which is an analogue ofSEQ ID No: 1 wherein said analogue comprises a proline residue atposition 21, a proline residue at position 27, an arginine residue atposition 17, an aspartic acid residue at position 14 and an arginineresidue at position 35, wherein the amino acid sequence numbering of theanalogue corresponds to the amino acid numbering sequence of SEQ IDNo: 1. Optionally, the polypeptide has an IC₅₀ in a human amylinreceptor binding assay (such as that disclosed herein) of about 1200 pMor less. Optionally the polypeptide has at least one substituentattached to at least one of its amino acid residues. The presentinvention also relates to pharmaceutical formulations comprising same.The present invention also relates to pharmaceutical uses of same. Thepresent invention also relates to the delivery (such as administration)of same to patients in need of treatment of same.

In another broad embodiment, the present invention relates to apolypeptide comprising an amino acid sequence which is an analogue ofSEQ ID No: 1 of formula (I):

(I) (SEQ ID NO: 5) Xaa₁-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Xaa₁₄-Phe-Leu-Xaa₁₇-His-Ser-Ser-Xaa₂₁-Asn-Phe-Gly-Xaa₂₅-Xaa₂₆-Xaa₂₇-Xaa₂₈-Xaa₂₉-Thr-Xaa₃₁-Val-Gly-Xaa₃₄-Xaa₃₅-Thr-Xaa₃₇;wherein

-   -   Xaa₁ is independently selected from Ala, Cys, Glu, Gly, His,        Arg, Ser and Lys;    -   Xaa₁₄ is independently selected from Asp, Glu, His, Asn, Arg,        Gly, Ala, Ser, Lys, Thr and Cys;    -   Xaa₁₇ is independently selected from Arg and Val;    -   Xaa₂₁ is Pro;    -   Xaa₂₅ is independently selected from Pro and Ala;    -   Xaa₂₆ is independently selected from Pro and Ile;    -   Xaa₂₇ is independently selected from Pro and Leu;    -   Xaa₂₈ is independently selected from Pro and Ser;    -   Xaa₂₉ is independently selected from Pro and Ser;    -   Xaa₃₁ is independently selected from Pro and Asn;    -   Xaa₃₄ is independently selected from Pro, His, Lys, Arg and Ser    -   Xaa₃₅ is independently selected from Asp, Arg, Glu, Lys, His and        Asn;    -   Xaa₃₇ is independently selected from Pro and Tyr;

and where the C-terminal may optionally be derivatized.

For the purpose of illustration, one example of formula (I) isAla-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asp-Phe-Leu-Arg-His-Ser-Ser-Pro-Asn-Phe-Gly-Pro-Pro-Pro-Pro-Pro-Thr-Pro-Val-Gly-Pro-Asp-Thr-Pro(SEQ ID NO: 2)

The present invention also relates to pharmaceutical formulationscomprising same. The present invention also relates to pharmaceuticaluses of same. The present invention also relates to the delivery (suchas administration) of same to patients in need of treatment of same.

In one embodiment, the present invention concerns a polypeptidecomprising an amino acid sequence which is an analogue of SEQ ID No: 1wherein:

-   -   (a) said analogue comprises a proline residue at position 21;        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1;    -   optionally wherein (b) the polypeptide has an IC₅₀ in a human        amylin receptor binding assay of about 1200 pM or less;    -   optionally wherein the polypeptide has at least one substituent        attached to at least one of its amino acid residues.

In one embodiment, the present invention concerns a polypeptidecomprising an amino acid sequence which is an analogue of SEQ ID No: 1wherein:

-   -   (a) said analogue comprises a proline residue at position 21;        and    -   (b) said polypeptide has an IC₅₀ in a human amylin receptor        binding assay of about 1200 pM or less;        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1.

In one embodiment, the present invention concerns a polypeptidecomprising an amino acid sequence which is an analogue of SEQ ID No: 1wherein:

-   -   (a) said analogue comprises a proline residue at position 21,        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1; and    -   wherein the polypeptide has at least one substituent attached to        at least one of its amino acid residues.

In one embodiment, the present invention concerns a polypeptidecomprising an amino acid sequence which is an analogue of SEQ ID No: 1wherein:

-   -   (a) said analogue comprises a proline residue at position 21;        and    -   (b) said polypeptide has an IC₅₀ in a human amylin receptor        binding assay of about 1200 pM or less;        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1; and    -   wherein the polypeptide has at least one substituent attached to        at least one of its amino acid residues.

In another embodiment, the invention further comprises a pharmaceuticalcomposition comprising the above polypeptide.

In another embodiment, the invention further comprises a process forpreparing a pharmaceutical composition comprising the above polypeptide.

In another embodiment, the invention further comprises the abovepolypeptide for use as a medicament.

The polypeptides of the present invention are advantageous as theypossess an increased selectivity for the amylin receptor.

A suitable human amylin receptor binding assay to determine the IC₅₀ isdescribed herein. For example, see Assay (V).

FIG. 1 presents a Table of a series of polypeptides according to thepresent invention.

FIG. 2 presents a structure of human amylin.

FIG. 3 presents a structure of gammaGlu.

FIG. 4 presents a structure of epsilon amino group and alpha aminogroup.

FIG. 5 presents a structure of pralintide.

In addition, FIG. 1 presents data for the recited polypeptides. In theTable of compounds shown in FIG. 1 the term “sequence modifications”means modifications with respect to human amylin.

In summary FIGS. 6 to 16 present that salmon calcitonin has comparablebinding affinities to amylin receptors and calcitonin receptors. Thus,salmon calcitonin mediates both decrease in plasma calcium (below 1.7mM) and reduction of food intake when administered to rats (dose 30nmol/kg). This is in contrast to the polypeptides of the presentinvention, which are improved amylin selective compounds and able toreduce food intake with only minimal decrease of plasma calcium (seeFIGS. 6 to 16).

In the Tables and FIG. 1: the term “acylation site” means the attachmentsite of the albumin binding moiety or linker to the polypeptide; theterm “N-terminal” means that it is attached to the alpha amino group ofthe N-terminal amino acid of the polypeptide sequence; the term “1K”means that it is attached to the epsilon amino group of the lysine inposition 1 of the sequence; the term “21K” means that it is attached tothe epsilon amino group of the lysine in position 21 of the polypeptidesequence; the term “−1K” means that it is attached to the epsilon aminogroup of the lysine in position −1, i.e. adjacent position 1; the term“sequence modifications” means modifications with respect to humanamylin.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 presents a Table of a series of polypeptides according to thepresent invention.

FIG. 2 presents a structure of human amylin.

FIG. 3 presents a structure of gammaGlu.

FIG. 4 presents a structure of epsilon amino group and alpha aminogroup.

FIG. 5 presents a structure of pramlintide.

FIG. 6 Effect from single subcutaneous administration of examplecompound on plasma calcium in rats (ASSAY XI), food intake monitoredover 48 hours after injecting vehicle or example 86 compound. Thecompound according to the present invention reduces food intake in rats,vehicle does not.

FIG. 7 Effect from single subcutaneous administration of examplecompound on plasma calcium in rats (ASSAY XI), food intake monitoredover 48 hours after injecting vehicle or example 89 or example 106compound. The compounds according to the present invention reduce foodintake in rats, vehicle does not.

FIG. 8 Effect from single subcutaneous administration of examplecompound on plasma calcium in rats (ASSAY XI) on food intake in rats,food intake monitored over 48 hours after injecting vehicle or example109. The compound according to the present invention reduces food intakein rats, vehicle does not.

FIG. 9 Effect from single subcutaneous administration of examplecompound on plasma calcium in rats (ASSAY XI) on food intake in rats,food intake monitored over 48 hours after injecting vehicle or example52. The compound according to the present invention reduces food intakein rats, vehicle does not.

FIG. 10 Effect from single subcutaneous administration of examplecompound on plasma calcium in rats (ASSAY XI) on food intake in rats,food intake monitored over 48 hours after injecting vehicle or example110 or example 117 compound. The compound according to the presentinvention reduces food intake in rats, vehicle does not.

FIG. 11 Effect from single subcutaneous administration of examplecompound on plasma calcium in rats (ASSAY XI) on food intake in rats,food intake monitored over 48 hours after injecting vehicle or salmoncalcitonin. Calcitonin reduces food intake in rats, vehicle does not.

FIG. 12 Effect from single subcutaneous administration of examplecompound on plasma calcium in rats (ASSAY XII), calcium levels monitoredover 24 hours after injecting vehicle or salmon calcitonin in 3different doses. 3 nmol/kg calcitonin supresses calcium levels aseffective as 30 nmol/kg and 300 nmol/kg calcitonin relative to vehiclecalcium levels.

FIG. 13 Effect from single subcutaneous administration of examplecompound on plasma calcium in rats (ASSAY XII), calcium levels monitoredover 24 hours after injecting vehicle or example 86 compound inincreasing doses. None of the doses trigger a notable suppression of thecalcium level relative to vehicle calcium levels.

FIG. 14 Effect from single subcutaneous administration of examplecompound on plasma calcium in rats (ASSAY XII), calcium levels monitoredover 24 hours after injecting vehicle or example 109 compound inincreasing doses or 100 nmol/kg of example 2 compound. At 3 nmol/kgexample 109 compound does not trigger a notable suppression of thecalcium level relative to vehicle calcium levels. At 30 nmol/kg example109 compound injection induces a minor suppression of the calcium levelcalcium level relative to vehicle calcium levels, however not aseffective as calcitonin at the same concentration (see FIG. 7/11). At100 and 300 nmol/kg example 109 compound induces a more pronouncedsuppression of the calcium level calcium level relative to vehiclecalcium levels, which is comparable to the suppression of calcium levelsseen by calcitonin at 3 nmol/kg. 100 nmol/kg of example 2 compound doesnot trigger a notable suppression of the calcium level relative tovehicle calcium levels not trigger a notable suppression of the calciumlevel relative to vehicle calcium levels.

FIG. 15 Effect from single subcutaneous administration of examplecompound on plasma calcium in rats (ASSAY XII), calcium levels monitoredover 24 hours after injecting vehicle or 30 nmol/kg example 51, 89, 110or 117 compound or 1000 nmol/kg example 89 compound. None of the examplecompounds at 30 nmol/kg trigger a notable suppression of the calciumlevel relative to vehicle calcium levels 1000 nmol/kg example 89compound induces a more pronounced suppression of the calcium levelcalcium level relative to vehicle calcium levels, which is comparable tothe suppression of calcium levels seen by calcitonin at 3 nmol/kg.

FIG. 16 Effect from single subcutaneous administration of examplecompound on plasma calcium in rats (ASSAY XII), calcium levels monitoredover 24 hours after injecting vehicle or example 52 compounds inincreasing doses. None of the doses trigger a notable suppression of thecalcium level relative to vehicle calcium levels.

DEFINITIONS

The term “human amylin” as used herein relates to the polypeptide humanamylin having the sequence as depicted in SEQ ID No 1. The termincludes, but is not limited to, a human polypeptide hormone of 37 aminoacids referred to as amylin, which in nature is co-secreted with insulinfrom n-cells of the pancreas. Human amylin has the following primaryamino acid sequence:

Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser-Asn-Asn-Phe-Gly-Ala-Ile-Leu-Ser-Ser-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr(SEQ ID NO: 1)

Human amylin has a disulfide bridge between the two Cys residues and aC-terminal amide group. This structure is shown below and also in FIG.2.

Herein, SEQ ID No: 1 and human amylin may be used interchangeably.

The term “amylin peptide”, “amylin polypeptide” or “amylin protein” asused herein refers to a human amylin, an amylin analogue or and/or anamylin derivative. The terms “peptide”, “polypeptide” or “protein” usedherein are referring to amylin, unless different is indicated. The term“analogue of amylin” or “amylin analogue” as used herein refers to avariant of SEQ ID No: 1.

For instance, said variants include, but are not limited to, one or moresubstitution and/or one or more deletion and/or one or more addition ofany one of the amino acid residues for any natural or unnatural aminoacid, synthetic amino acids or peptidomimetics and/or the attachment ofa substituent to any one of the natural or unnatural amino acids,synthetic amino acids or peptidomimetics at any available position. Incase of an attachment of a substituent to any one of the natural orunnatural amino acids, synthetic amino acids or peptidomimetics at anyavailable position in the amylin analogue or peptide as defined above,the resulting amylin polypeptidemay then also be referred to herein as“a amylin derivative”, “a derivative according to the presentinvention”, “derivative of amylin” or “derivative of a peptide”.

The variant may have the same number of amino acid residues as humanamylin (i.e. 37). Alternatively, the variant may comprise less aminoacid residues than human amylin. Alternatively, the variant may comprisemore amino acid residues than human amylin. In some embodiments, thevariant has the same number of amino acid residues as human amylin (i.e.37). In some embodiments, the variant includes substitutions of any oneof the amino acid residues for any natural or unnatural amino acid,synthetic amino acids or peptidomimetics and/or the attachment of asubstituent to any one of the natural or unnatural amino acids,synthetic amino acids or peptidomimetics at any available position.

If the analogue contains either more than 37 amino acid residues or lessthan 37 amino acid residues then the skilled person can still align thatsequence with the sequence of human amylin (SEQ ID No. 1) to determinethe placement number of the corresponding, respective amino acidresidue. A suitable alignment program is “needle”, which is aNeedleman-Wunsch alignment. The alogorithm for this alignment program isdescribed in Needleman, S. B. and Wunsch, C. D., (1970), Journal ofMolecular Biology, 48: 443-453.

The polypeptide may comprise one or more amino acid substitutions.Hence, for some embodiments, the number of amino acid substitutions inthe amylin analogue may be at least one. Preferably, the number of aminosubstitutions is between one and fifteen, more preferably between oneand twelve, more preferably still between one and nine, more preferablystill between one and five.

The polypeptide may comprise one or more substituents on one or more ofthe amino acid residues. The term “amylin derivative” as used hereinrefers to an amylin polypeptide (including human amylin and amylinanalogues as defined above), comprising one or more substituents on oneor more of the amino acid residues.

The term “substituent” as used herein means any suitable moiety bonded,in particular covalently bonded, to an amino acid residue, in particularto any available position on an amino acid residue. Typically, thesuitable moiety is a chemical moiety.

For some embodiments, the substituent comprises a linker.

For some embodiments, the polypeptide has a substituent on one aminoacid residue, which amino acid residue is either the amino acid residuein the N-terminal residue or the amino acid residue is a Lysine.

For some embodiments, the polypeptide has a substituent on theN-terminal amino acid residue bound via the α-amino group of theN-terminal amino acid residue.

For some embodiments, the N-terminal amino acid residue is Lysine andthe polypeptide has a substituent on the N-terminal amino acid residuebound via the ε-amino group of the lysine amino residue.

For some embodiments, the polypeptide is extended by addition of aLysine residue at the N-terminal and the polypeptide has a substituenton the N-terminal amino acid residue bound via the ε-amino group of thelysine amino residue.

For some embodiments, the polypeptide is extended by addition of anamino acid residue at the N-terminal and the polypeptide has asubstituent on the N-terminal amino acid residue bound via the α-aminogroup of the N-terminal amino acid residue.

For some embodiments, substitution by acylation in the epsilon aminogroup of Lys1 versus the alpha amino group surprisingly leads to animprovement in selectivity, such as to levels of about 1.5 to 5 fold.

In the numbering sequence of SEQ ID No: 1, and according to establishedpractice in the art, the amino acid residue at the N-terminal (Lys) isassigned no. 1 and subsequent amino acid residues are numberedconsecutively, ending at the C-terminal with tyrosine assigned no. 37.Therefore, generally, any reference herein to position number of anamino acid residue provides its location in a 37 amino acid sequence;said 37 amino acid sequence being an analogue of human amylin. Forexample, a reference to an analogue modified at position 21 refers to ananalogue wherein the 21^(st) amino residue out of the 37 amino acids inthe analogue has been modified.

In other words, the amino acid sequence numbering of the analogueprovides the position of each analogue with respect to a 37 amino acidsequence, wherein the numbering is consecutive and ascending in thedirection from the N-terminal to the C-terminal.

Analogues may be described by reference to the number of the amino acidresidue in human amylin which is modified, i.e. by its position, and thenature of the modification. The following are non-limiting examples ofappropriate analogue nomenclature.

For example:

-   -   Pro21 human amylin designates an analogue of human amylin        wherein the modification from human amylin is the Asn at        position 21 which has been substituted with Pro.    -   Pro21 human amylin designates an analogue of human amylin        wherein the modification from human amylin is the Asn at        position 21 of the human amylin sequence (SEQ ID NO 1) which has        been substituted with Pro.    -   Pro21 Pro27 human amylin designates an analogue of human amylin        wherein the modifications from human amylin are that the Asn at        position 21 and the Leu at position 27 have both been        substituted with Pro.    -   Pro21 Pro27 human amylin designates an analogue of human amylin        wherein the modifications from human amylin are that the Asn at        position 21 of the human amylin sequence (SEQ ID NO 1) and the        Leu at position 27 have both been substituted with Pro.

As is apparent from the above examples, amino acid residues may beidentified by their full name, their one-letter code, and/or theirthree-letter code. These three ways are fully equivalent.

The expressions “conforms to”, “corresponds to”, “a position equivalentto” or “corresponding position” may be used to characterise the site ofmodification in an analogue of human amylin by reference to SEQ IDNo: 1. Equivalent or corresponding positions are easily deduced, e.g. bysimple handwriting and eyeballing; and/or a standard protein orpolypeptide alignment program may be used, such as “needle” which is aNeedleman-Wunsch alignment. The algorithm is described in Needleman, S.B. and Wunsch, C. D., (1970), Journal of Molecular Biology, 48: 443-453,and the align program by Myers and W. Miller in “Optimal Alignments inLinear Space” CABIOS (computer applications in the biosciences) (1988)4:11-17. For the alignment, the default scoring matrix BLOSUM62 and thedefault identity matrix may be used, and the penalty for the firstresidue in a gap may be set at −10 and the penalties for additionalresidues in a gap at −0.5.

When used herein the term “natural amino acid” is an amino acid (withthe usual three letter codes & one letter codes in parenthesis) selectedfrom the group consisting of: Glycine (Gly & G), proline (Pro & P),alanine (Ala & A), valine (Val & V), leucine (Leu & L), isoleucine (Ile& I), methionine (Met & M), cysteine (Cys & C), phenylalanine (Phe & F),tyrosine (Tyr & Y), tryptophan (Trp & W), histidine (His & H), lysine(Lys & K), arginine (Arg & R), glutamine (Gln & Q), asparagine (Asn &N), glutamic acid (Glu & E), aspartic acid (Asp & D), serine (Ser & S)and threonine (Thr & T). If, due to typing errors, there are deviationsfrom the commonly used codes, the commonly used codes apply. The aminoacids present in the polypeptides of the present invention are,preferably, amino acids which can be coded for by a nucleic acid.

As used herein, the term “hydrocarbyl” refers to a group comprising atleast carbon and hydrogen that may optionally comprise one or more othersuitable substituents. Examples of such substituents may includehydroxy, alkyl, halo, alkoxy, haloalkyl, haloalkoxy, amino, aminoalkylor a cyclic group. In addition to the possibility of the substituentsbeing a cyclic group, a combination of substituents may form a cyclicgroup. If the hydrocarbyl group comprises more than one carbon atom thenthose carbon atoms need not necessarily be linked to each other. Forexample, at least two of the carbon atoms may be linked via a suitableatom or group. Thus, the hydrocarbyl group may contain heteroatoms.Suitable heteroatoms will be apparent to those skilled in the art andinclude, for instance, sulphur, nitrogen, oxygen, phosphorus andsilicon. In one embodiment the hydrocarbyl group is selected from thegroup consisting of an alkyl group, an alkenyl group, an alkynyl group,an aryl group, a heteroaryl group or a cycloalkyl group, each of whichmay be optionally substituted. Examples of such substituents may includehydroxy, alkyl, halo, alkoxy, haloalkyl, haloalkoxy, amino, aminoalkyl,or a cycloalkyl group.

As used herein, the term “alkyl” includes both saturated straight chainand branched alkyl groups which may be substituted (mono- or poly-) orunsubstituted. Preferably, the alkyl group is a C₁₋₂₀ alkyl group, morepreferably a C₁₋₁₅, more preferably still a C₁₋₁₀ alkyl group, morepreferably still a C₁₋₈ alkyl group, more preferably still a C₁₋₈ alkylgroup. Particularly preferred alkyl groups include, for example, methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, n-hexyl, n-heptyl and n-octyl. Suitable substituents include,for example, hydroxy, alkyl, halo, alkoxy, haloalkyl, haloalkoxy, amino,aminoalkyl, or a cycloalkyl group.

As used herein, the term “cycloalkyl” refers to a cyclic alkyl groupwhich may be substituted (mono- or poly-) or unsubstituted. Suitablesubstituents include, for example, hydroxy, alkyl, halo, alkoxy,haloalkyl, haloalkoxy, amino, aminoalkyl, or a cycloalkyl group.

As used herein, the term “alkenyl” refers to a carbon chain containingone or more carbon-carbon double bonds, which may be branched orunbranched, and substituted (mono- or poly-) or unsubstituted.Preferably the alkenyl group is a C₂₋₂₀ alkenyl group, more preferably aC₂₋₁₅ alkenyl group, more preferably still a C₂₋₁₀ alkenyl group, morepreferably still a C₂₋₈ alkenyl group, or more preferably still a C₂₋₆alkenyl group. Suitable substituents include, for example, hydroxy,alkyl, halo, alkoxy, haloalkyl, haloalkoxy, amino, aminoalkyl, or acycloalkyl group.

As used herein, the term “alkynyl” refers to a carbon chain containingone or more carbon-carbon triple bonds, which may be branched orunbranched, and substituted (mono- or poly-) or unsubstituted.Preferably the alkynyl group is a C₂₋₂₀ alkynyl group, more preferably aC₂₋₁₅ alkynyl group, more preferably still a C₂₋₁₀ alkynyl group, morepreferably still a C₂₋₈ alkynyl group, or more preferably still a C₂₋₆alkynyl group. Suitable substituents include, for example, hydroxy,alkyl, halo, alkoxy, haloalkyl, haloalkoxy, amino, aminoalkyl, or acycloalkyl group.

As used herein, the term “aryl” refers to a C₆₋₁₀ aromatic group whichmay be substituted (mono- or poly-) or unsubstituted. Typical examplesinclude phenyl and naphthyl etc.

Suitable substituents include, for example, hydroxy, alkyl, halo,alkoxy, haloalkyl, haloalkoxy, amino, aminoalkyl, or a cycloalkyl group.

As used herein, the term “heteroaryl” refers to an aryl group as definedabove which contains one or more heteroatoms. Suitable heteroatoms willbe apparent to those skilled in the art and include, for example,sulphur, nitrogen, oxygen, phosphorus and silicon. Suitable substituentsinclude, for example, hydroxy, alkyl, halo, alkoxy, haloalkyl,haloalkoxy, amino, aminoalkyl, or a cycloalkyl group.

The term “linker” as used herein includes suitable substituents that canjoin a moiety, such as a chemical moiety, to the polypeptide, such asthe polypeptide backbone. Thus, the linker and the chemical moietybecome a substituent together. The moiety joined to the linker may beany suitable moiety. Examples include an albumin binding moiety,—(CH₂)_(s)—COON, where s is an integer from 12 to 20. Other examplesinclude albumin binding moieties such as —(CH₂)_(n)—CH₃, where s is aninteger from 12 to 20, sulfonic moieties such as —(CH₂)_(s)—SO₃H, wheres is an integer from 12 to 20, and tetrazoles such as —(CH₂)_(s)—CN₄Hwhere s is an integer from 12 to 20.

In one embodiment the moiety joined to the linker is an albumin bindingmoiety.

For example, the linker can comprise one or two amino acids which at oneend bind to the moiety—such as an albumin binding moiety—and at theother end bind to any available position on the polypeptide backbone.

In some embodiments, the linker provides a bridge or link between anamino group on the polypeptide backbone and an acyl group on themoiety—such as an albumin binding moiety.

The linker may be bound to, or near to, the N terminal amino acidresidue. Preferably the linker is bound to the amino acid in position 1of the amylin analogue.

Another example of a linker is a combination of at least one amino acidand an amine.

In an embodiment, preferably the amine is the group OEG, wherein theformula of OEG is shown below:

For some embodiments, preferably the linker is selected from the groupconsisting of γGlu, γGlu-γGlu, γGlu-γGlu-γGlu, γGlu-γGlu-γGlu-γGlu, Glu,Glu-Glu, Glu-γGlu, Glu-Arg, Glu-Glu-Arg, His, His-His, His-γGlu,His-His-γGlu, Gly, Gly-γGlu, Ser, Ser-γGlu, D-Arg-D-Arg, Arg, Arg-Arg,Arg-Arg-γGlu, Ser-Ser, -Gly-Ser-Ser, Ser-Ser, -Gly-Ser-Ser-γGlu,Ser-Ser-Gly-Ser-Ser-Gly and Ser-Ser-Gly-Ser-Ser-Gly-γGlu, γGlu-OEG,γGlu-2×OEG and OEG, preferably the linker is selected from γGlu,γGlu-γGlu, γGlu-OEG, γGlu-2×OEG and OEG, more preferably the linker isγGlu-γGlu.

The linker can contribute to and/or enhance the binding effect of themoiety (for example the albumin binding moiety), e.g. a linkercomprising γGlu can enhance the albumin binding effect of thepolypeptide.

By using the term “γGlu” or “gGlu” or “gammaGlu” or “gamma-L-Glu” ismeant an amino acid with the following structure (also shown in FIG. 3):

By using the term “γGlu-γGlu” is meant moiety with the followingstructure:

By using the term “γGlu-OEG” is meant a moiety with the followingstructure:

By using the term “γGlu-OEG-OEG” is meant moiety with the followingstructure:

The term “epilson amino group” or “E-amino group”, used herein inrelation to lysine, refers to the amino group at the 6 position, usingthe IUPAC standard numbering conventions. The term “alpha amino group”or “α-amino group” refers to the amino group at the 2 position, usingthe IUPAC standard numbering conventions. We refer to the followingstructure (also shown in FIG. 4).

The term “albumin binding moiety” as used herein refers to any chemicalgroup capable of binding to albumin, i.e. has albumin binding affinity.In one embodiment the albumin binding moiety is an acyl group.

In some embodiments, preferably the albumin binding moiety is an acylgroup selected from:

-   -   (a) CH₃(CH₂)_(r)CO—, wherein r is an integer from 12 to 20;    -   (b) HOOC(CH₂)_(s)CO—, wherein s is an integer from 12 to 22.

“Albumin binding affinity” may be determined by several methods knownwithin the art. In one method the compound to be measured isradiolabeled with e.g. ¹²⁵I or ³H and incubated with immobilized albumin(Kurtzhals et. al., Biochem. J., 312, 725-731 (1995)). The binding ofthe compound relative to a standard is calculated. In another method arelated compound is radiolabeled and its binding to albumin immobilizedon e.g. SPA beads is competed by a dilution series of the compound to bemeasured. The EC₅₀ value for the competition is a measure of theaffinity of the compound. In a third method, the receptor affinity orpotency of a compound is measured at different concentrations ofalbumin, and the shift in relative affinity or potency of the compoundas a function of albumin concentration reflects its affinity foralbumin.

The polypeptides of the present invention exhibit good potency. The term“potency” is used to describe the effect of a given compound in assayswhere a sigmoidal relationship between log concentration and the effectof a compound has been established. Furthermore, the response should bevariable from 0 to 100%. EC (effective concentration)₅₀ can be used todescribe the concentration of a given compound yielding a response of50% in the assay, such as in the functional assay.

The polypeptides of the present invention exhibit good activity. Theterm “activity” refers to the ability to reduce appetite and/or increasesatiety. The activity can be measured by the ability to reduce appetiteas e.g. described in the Assay (I) herein.

The polypeptides of the present invention exhibit good physicalstability. The term “physical stability” of a polypeptide according tothe invention, or a formulation thereof refers to the tendency of thepolypeptide not to form biologically inactive and/or insolubleaggregates as a result of exposure to thermo-mechanical stresses and/orinteraction with interfaces and surfaces that are destabilizing, such ashydrophobic surfaces and interfaces. Physical stability of the aqueouspolypeptide formulations may be evaluated by means of visual inspection,ThT fibrillation assay (sometimes referred to as a ThT fibrillogenesisassay) and/or turbidity measurements as described elsewhere herein.Visual inspection of the formulations is performed in a sharp focusedlight with a dark background. The turbidity of the formulation ischaracterized by a visual score ranking the degree of turbidity forinstance on a scale from 0 to 3 (a formulation showing no turbiditycorresponds to a visual score 0, and a formulation showing visualturbidity in daylight corresponds to visual score 3). A formulation isclassified physical unstable with respect to protein aggregation, whenit shows visual turbidity in daylight. Alternatively, the turbidity ofthe formulation can be evaluated by simple turbidity measurementswell-known to the skilled person.

The polypeptides of the present invention exhibit good chemicalstability. The term “chemical stability” of a polypeptide according tothe invention or of a formulation thereof refers to no chemical covalentchanges in the polypeptide structure hence avoiding the formation ofchemical degradation products with potentially less potency and/orpotentially increased immunogenic properties compared to the parent(native) polypeptide structure. Various chemical degradation productscan be formed depending on the type and nature of the parent polypeptideand the environment to which the polypeptide is exposed. Elimination ofchemical degradation can most probably not be completely avoided andincreasing amounts of chemical degradation products is often seen duringstorage and use of the polypeptide formulations as well-known by theperson skilled in the art. Most polypeptides are prone to deamidation, aprocess in which the side chain amide group in glutaminyl or asparaginylresidues is hydrolysed to form a free carboxylic acid. Otherdegradations pathways involves formation of high molecular weighttransformation products where two or more polypeptide molecules arecovalently bound to each other through transamidation and/or disulfideinteractions leading to formation of covalently bound dimer, oligomerand polymer degradation products (Stability of Protein Pharmaceuticals,Ahern. T. J. & Manning M. C., Plenum Press, New York 1992). Oxidation(of for instance methionine residues) can be mentioned as anothervariant of chemical degradation. The chemical stability of thepolypeptide formulation can be evaluated by measuring the amount of thechemical degradation products at various time-points after exposure todifferent environmental conditions (the formation of degradationproducts can often be accelerated by for instance increasingtemperature). The amount of each individual degradation product is oftendetermined by separation of the degradation products depending onmolecule size and/or charge using various chromatography techniques(e.g. SEC-HPLC and/or RP-HPLC).

The term “stabilized formulation” refers to a formulation with increasedphysical stability, increased chemical stability or increased physicaland chemical stability compared to an aqueous solution of thepolypeptide.

DESCRIPTION OF THE INVENTION General Embodiments

In one embodiment, the present invention relates to a polypeptidecomprising an amino acid sequence which is an analogue of SEQ ID No: 1wherein:

-   -   (a) said analogue comprises a proline residue at position 21;        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1;    -   optionally wherein (b) the polypeptide has an IC₅₀ in a human        amylin receptor binding assay of about 1200 pM or less;    -   optionally wherein the polypeptide has at least one substituent        attached to at least one of its amino acid residues.

In one specific embodiment, the present invention relates to apolypeptide comprising an amino acid sequence which is an analogue ofSEQ ID No: 1 wherein:

-   -   (a) said analogue comprises a proline residue at position 21;        and    -   (b) said polypeptide has an IC₅₀ in a human amylin receptor        binding assay of about 1200 pM or less;        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1.

In another embodiment, the present invention relates to a polypeptidecomprising an amino acid sequence which is an analogue of SEQ ID No: 1wherein:

-   -   (a) said analogue comprises a proline residue at position 21;        and    -   (b) said analogue comprises a proline residue at position 27;        and    -   (c) optionally wherein said polypeptide has an IC₅₀ in a human        amylin receptor binding assay of about 1200 pM or less;        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1.

In another embodiment, the present invention relates to a polypeptidecomprising an amino acid sequence which is an analogue of SEQ ID No: 1wherein:

-   -   (a) said analogue comprises a proline residue at position 21;        and    -   (b) said analogue comprises a proline residue at position 27;        and    -   (c) said analogue comprises an arginine residue at position 17;        and    -   (d) optionally wherein said polypeptide has an IC₅₀ in a human        amylin receptor binding assay of about 1200 pM or less;        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1.

In another embodiment, the present invention relates to a polypeptidecomprising an amino acid sequence which is an analogue of SEQ ID No: 1wherein:

-   -   (a) said analogue comprises a proline residue at position 21;        and    -   (b) said analogue comprises a proline residue at position 27;        and    -   (c) said analogue comprises an arginine residue at position 17;        and    -   (d) said analogue comprises an aspartic acid residue at position        14; and    -   (e) optionally wherein said polypeptide has an IC₅₀ in a human        amylin receptor binding assay of about 1200 pM or less;        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1.

In another embodiment, the present invention relates to a polypeptidecomprising an amino acid sequence which is an analogue of SEQ ID No: 1wherein:

-   -   (a) said analogue comprises a proline residue at position 21;        and    -   (b) said analogue comprises a proline residue at position 27;        and    -   (c) said analogue comprises an arginine residue at position 17;        and    -   (d) said analogue comprises an aspartic acid residue at position        14; and    -   (e) said analogue comprises an arginine residue at position 35;        and    -   (f) optionally wherein said polypeptide has an IC₅₀ in a human        amylin receptor binding assay of about 1200 pM or less;        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1.

In another embodiment, the present invention relates to a polypeptidecomprising an amino acid sequence which is an analogue of SEQ ID No: 1of formula (I):

(I) Xaa₁-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Xaa₁₄-Phe-Leu-Xaa₁₇-His-Ser-Ser-Xaa₂₁-Asn-Phe-Gly-Xaa₂₅-Xaa₂₆-Xaa₂₇-Xaa₂₈-Xaa₂₉-Thr-Xaa₃₁-Val-Gly-Xaa₃₄-Xaa₃₅-Thr-Xaa₃₇;wherein

-   -   Xaa₁ is independently selected from Ala, Cys, Glu, Gly, His,        Arg, Ser and Lys;    -   Xaa₁₄ is independently selected from Asp, Glu, His, Asn, Arg,        Gly, Ala, Ser, Lys, Thr and Cys;    -   Xaa₁₇ is independently selected from Arg and Val;    -   Xaa₂₁ is Pro;    -   Xaa₂₅ is independently selected from Pro and Ala;    -   Xaa₂₆ is independently selected from Pro and Ile;    -   Xaa₂₇ is independently selected from Pro and Leu;    -   Xaa₂₈ is independently selected from Pro and Ser;    -   Xaa₂₉ is independently selected from Pro and Ser;    -   Xaa₃₁ is independently selected from Pro and Asn;    -   Xaa₃₄ is independently selected from Pro, His, Lys, Arg and Ser    -   Xaa₃₅ is independently selected from Asp, Arg, Glu, Lys, His and        Asn;    -   Xaa₃₇ is independently selected from Pro and Tyr;    -   and where the C-terminal may optionally be derivatized;        and wherein said polypeptide has an IC₅₀ in a human amylin        receptor binding assay of about 1200 pM or less.

In one embodiment, the present invention relates to a polypeptide whichis an analogue of SEQ ID No: 1 wherein:

-   -   (a) said analogue comprises a proline residue at position 21;        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1;    -   optionally wherein (b) the polypeptide has an IC₅₀ in a human        amylin receptor binding assay of about 1200 pM or less;    -   optionally wherein the polypeptide has at least one substituent        attached to at least one of its amino acid residues.

In one specific embodiment, the present invention relates to apolypeptide which is an analogue of SEQ ID No: 1 wherein:

-   -   (a) said analogue comprises a proline residue at position 21;        and    -   (b) said polypeptide has an IC₅₀ in a human amylin receptor        binding assay of about 1200 pM or less;        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1.

In another embodiment, the present invention relates to a polypeptidewhich is an analogue of SEQ ID No: 1 wherein:

-   -   (a) said analogue comprises a proline residue at position 21;        and    -   (b) said analogue comprises a proline residue at position 27;        and    -   (c) optionally wherein said polypeptide has an IC₅₀ in a human        amylin receptor binding assay of about 1200 pM or less;        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1.

In another embodiment, the present invention relates to a polypeptidewhich is an analogue of SEQ ID No: 1 wherein:

-   -   (a) said analogue comprises a proline residue at position 21;        and    -   (b) said analogue comprises a proline residue at position 27;        and    -   (c) said analogue comprises an arginine residue at position 17;        and    -   (d) optionally wherein said polypeptide has an IC₅₀ in a human        amylin receptor binding assay of about 1200 pM or less;        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1.

In another embodiment, the present invention relates to a which is ananalogue of SEQ ID No: 1 wherein:

-   -   (a) said analogue comprises a proline residue at position 21;        and    -   (b) said analogue comprises a proline residue at position 27;        and    -   (c) said analogue comprises an arginine residue at position 17;        and    -   (d) said analogue comprises an aspartic acid residue at position        14; and    -   (e) optionally wherein said polypeptide has an IC₅₀ in a human        amylin receptor binding assay of about 1200 pM or less;        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1.

In another embodiment, the present invention relates to a polypeptidewhich is an analogue of SEQ ID No: 1 wherein:

-   -   (a) said analogue comprises a proline residue at position 21;        and    -   (b) said analogue comprises a proline residue at position 27;        and    -   (c) said analogue comprises an arginine residue at position 17;        and    -   (d) said analogue comprises an aspartic acid residue at position        14; and    -   (e) said analogue comprises an arginine residue at position 35;        and    -   (f) optionally wherein said polypeptide has an IC₅₀ in a human        amylin receptor binding assay of about 1200 pM or less;        wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1.

In another embodiment, the present invention relates to a polypeptidewhich is an analogue of SEQ ID No: 1 of formula (I):

(I) Xaa₁-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Xaa₁₄-Phe-Leu-Xaa₁₇-His-Ser-Ser-Xaa₂₁-Asn-Phe-Gly-Xaa₂₅-Xaa₂₆-Xaa₂₇-Xaa₂₈-Xaa₂₉-Thr-Xaa₃₁-Val-Gly-Xaa₃₄-Xaa₃₅-Thr-Xaa₃₇;wherein

-   -   Xaa₁ is independently selected from Ala, Cys, Glu, Gly, His,        Arg, Ser and Lys;    -   Xaa₁₄ is independently selected from Asp, Glu, His, Asn, Arg,        Gly, Ala, Ser, Lys, Thr and Cys;    -   Xaa₁₇ is independently selected from Arg and Val;    -   Xaa₂₁ is Pro;    -   Xaa₂₅ is independently selected from Pro and Ala;    -   Xaa₂₆ is independently selected from Pro and Ile;    -   Xaa₂₇ is independently selected from Pro and Leu;    -   Xaa₂₈ is independently selected from Pro and Ser;    -   Xaa₂₉ is independently selected from Pro and Ser;    -   Xaa₃₁ is independently selected from Pro and Asn;    -   Xaa₃₄ is independently selected from Pro, His, Lys, Arg and Ser    -   Xaa₃₅ is independently selected from Asp, Arg, Glu, Lys, His and        Asn;    -   Xaa₃₇ is independently selected from Pro and Tyr;    -   and where the C-terminal may optionally be derivatized;        and wherein said polypeptide has an IC₅₀ in a human amylin        receptor binding assay of about 1200 pM or less.

Some Advantages

The polypeptides of the present invention exhibit improved physicalstability.

The polypeptides of the present invention possess improved selectivityfor amylin receptors over calcitonin receptors.

The polypeptides of the present invention possess improved selectivityfor human amylin receptors over human calcitonin receptors.

Some Preferred Embodiments

A suitable human amylin receptor binding assay to determine the IC₅₀ ispresented herein.

In one preferred embodiment, Xaa₂₁ is Pro. In one preferred embodiment,Xaa₂₁ is Pro and Xaa₂₇ is Pro. In one preferred embodiment Xaa₂₁ is Pro,Xaa₂₇ is Pro and Xaa₁₇ is Arg. In one preferred embodiment Xaa₂₁ is Pro,Xaa₂₇ is Pro, Xaa₁₇ is Arg and Xaa₁₄ is Asp. In one preferred embodimentXaa₂₇ is Pro, Xaa₁₇ is Arg, Xaa₁₄ is Asp and Xaa₃₅ is Arg. In onepreferred embodiment Xaa₂₁ is Pro, Xaa₂₇ is Pro, Xaa₁₇ is Arg, Xaa₁₄ isAsp and Xaa₃₅ is Arg. In one preferred embodiment Xaa₂₁ is Pro, Xaa₂₇ isPro, Xaa₁₇ is Arg, and Xaa₃₄ is His. In one preferred embodiment Xaa₂₁is Pro, Xaa₂₇ is Pro, Xaa₁₇ is Arg, Xaa₁₄ is Glu and Xaa₃₅ is Arg. Inone preferred embodiment Xaa₂₁ is Pro, Xaa₂₇ is Pro, Xaa₁₇ is Arg, Xaa₁₄is Glu, Xaa₃₄ is Pro and Xaa₃₅ is Glu. In one preferred embodiment Xaa₂₁is Pro, Xaa₂₇ is Pro, Xaa₁₇ is Arg, Xaa₁₄ is Glu, Xaa₃₄ is Pro and Xaa₃₅is His. In one preferred embodiment, Xaa₂₁ in a polypeptide according tothis invention and formula (I) is Pro.

In one preferred embodiment, Xaa₂₁ in a polypeptide according to thisinvention and formula (I) is Pro and Xaa₂₇ in a polypeptide according tothis invention and formula (I) is Pro. In one preferred embodiment Xaa₂₁in a polypeptide according to this invention and formula (I) is Pro,Xaa₂₇ in a polypeptide according to this invention and formula (I) isPro and Xaa₁₇ in a polypeptide according to this invention and formula(I) is Arg. In one preferred embodiment Xaa₂₁ in a polypeptide accordingto this invention and formula (I) is Pro, Xaa₂₇ in a polypeptideaccording to this invention and formula (I) is Pro, Xaa₁₇ in apolypeptide according to this invention and formula (I) is Arg and Xaa₁₄in a polypeptide according to this invention and formula (I) is Asp. Inone preferred embodiment Xaa₂₇ in a polypeptide according to thisinvention and formula (I) is Pro, Xaa₁₇ in a polypeptide according tothis invention and formula (I) is Arg, Xaa₁₄ in a polypeptide accordingto this invention and formula (I) is Asp and Xaa₃₅ in a polypeptideaccording to this invention and formula (I) is Arg. In one preferredembodiment Xaa₂₁ in a polypeptide according to this invention andformula (I) is Pro, Xaa₂₇ in a polypeptide according to this inventionand formula (I) is Pro, Xaa₁₇ is in a polypeptide according to thisinvention and formula (I) Arg, Xaa₁₄ in a polypeptide according to thisinvention and formula (I) is Asp and Xaa₃₅ in a polypeptide according tothis invention and formula (I) is Arg. In one preferred embodiment Xaa₂₁in a polypeptide according to this invention and formula (I) is Pro,Xaa₂₇ in a polypeptide according to this invention and formula (I) isPro, Xaa₁₇ in a polypeptide according to this invention and formula (I)is Arg, and Xaa₃₄ in a polypeptide according to this invention andformula (I) is His. In one preferred embodiment Xaa₂₁ in a polypeptideaccording to this invention and formula (I) is Pro, Xaa₂₇ in apolypeptide according to this invention and formula (I) is Pro, Xaa₁₇ ina polypeptide according to this invention and formula (I) is Arg, Xaa₁₄in a polypeptide according to this invention and formula (I) is Glu andXaa₃₅ in a polypeptide according to this invention and formula (I) isArg. In one preferred embodiment Xaa₂₁ is Pro, Xaa₂₇ in a polypeptideaccording to this invention and formula (I) is Pro, Xaa₁₇ in apolypeptide according to this invention and formula (I) is Arg, Xaa₁₄ ina polypeptide according to this invention and formula (I) is Glu, Xaa₃₄in a polypeptide according to this invention and formula (I) is Pro andXaa₃₅ in a polypeptide according to this invention and formula (I) isGlu. In one preferred embodiment Xaa₂₁ in a polypeptide according tothis invention and formula (I) is Pro, Xaa₂₇ in a polypeptide accordingto this invention and formula (I) is Pro, Xaa₁₇ in a polypeptideaccording to this invention and formula (I) is Arg, Xaa₁₄ in apolypeptide according to this invention and formula (I) is Glu, Xaa₃₄ ina polypeptide according to this invention and formula (I) is Pro andXaa₃₅ in a polypeptide according to this invention and formula (I) isHis. In one embodiment the C-terminal may be derivatized. In oneembodiment the C-terminal of an amylin peptide according to the presentinvention may be derivatized. The term “derivatized” as used hereinmeans, that a substituent is attached to an amino acid in said humanamylin, amylin analogue or amylin peptide as previously defined. Thus,when the C-terminal of an amylin peptide is derivatized, it is meantthat a substituent is attached to this amylin peptides C-terminus.

In one embodiment the C-terminal is derivatized with an amide of formula(II):

C(O)NR¹R²  (II)

wherein R¹ and R² are independently selected from H and alkyl.Preferably R¹ and R² are both H.

In one embodiment, polypeptides of the present invention may have asubstituent attached to any available position on one or more of theamino acid residues. Examples of substituents include chemical moietiesdirectly bound to one or more of the amino acid residues, or chemicalmoieties indirectly bound to one or more of the amino acid residues bymeans of a linker. Available points of attachment will be known to theskilled person. Examples of available attachment points include theN-terminal of the polypeptide, the C-terminal of the polypeptide, anepsilon-amino group of a Lysine residue, the hydroxyl group of a serine,tyrosine or threonine residue, the amide group of an asparagine orglutamine residue, the carboxyl group of an aspartic acid or glutamicacid residue, the thiol group of a cysteine residue. Preferably, thesubstituent is attached to the N-terminal of the polypeptide, or theepsilon amino group of a lysine residue.

The term “acylation” or “acylated” when used herein refers to asubstituent which is attached by the formation of an amide bond betweenan amino group on the peptide/analogue and a carboxylic acid on thesubstituent.

For some embodiments, we have found that acylation in the epsilon aminogroup of Lys1 versus the alpha amino group surprisingly leads to animprovement in selectivity of about 1.5 to 5 fold. To illustrate this,pairs of analogues with identical polypeptide sequences but differentacylation position can be compared. For example, we refer to any of:compound 18 vs compound 128, compound 16 vs compound 51, compound 8 vscompound 12, compound 21 vs compound 48, compound 39 vs compound 79,compound 71 vs compound 76.

In another embodiment the substitutent is attached to the N-terminalamino group of the polypeptide wherein the N-terminal amino acid residuecorresponds to position 1 of the analogue of SEQ ID No: 1.

In another embodiment the substitutent is attached to the epilson aminogroup of a lysine residue in position 1 of analogue of SEQ ID No: 1.

In one embodiment, the substituent is selected from a hydrocarbylsubstituent group, a hydroxyl group and a halogen atom. Examples ofsuitable halogen atoms include F, Cl, Br and I. Preferably, thesubstituent is a hydrocarbyl substituent group.

In another embodiment, the hydrocarbyl substituent group is an alkylgroup, or a group of formula (III):

L_(n)-Y  (III)

-   -   wherein        -   L is a linker;        -   n=0 or 1        -   Y is a chemical moiety—such as an albumin binding moiety.

In one embodiment the linker comprises 1 to 10 amino acids. The linkercan further comprise amines.

Examples of suitable amines include:

C(O)—(CH₂)_(l)—O—[CH₂CH₂—O]_(m)—(CH₂)_(p)[NHC(O)—(CH₂)_(l)—O—[(CH₂)_(n)—O]_(m)—(CH₂)_(p)]_(q)—NH—

-   -   wherein l, m, n, and p independently are 1-7, and q is 0-5.

For example the linker can comprise an amine selected from:

—C(O)—CH₂—O—CH₂—CH₂—O—CH₂—CH₂—NH—; and

—C(O)—CH₂—O—CH₂—CH₂—O—CH₂—CH₂—[NHC(O)—CH₂—O—CH₂—CH₂—O—CH₂—CH₂]₁—NH—; and

—C(O)—(CH₂)₂—O—[CH₂CH₂—O]₇—(CH₂)₂—NH—.

In another embodiment the linker is a combination of amino acid residuesand the above mentioned amines, for example:

γGlu-C(O)—CH₂—O—CH₂—CH₂—O—CH₂—CH₂—[NHC(O)—CH₂—O—CH₂—CH₂—O—CH₂—CH₂—]₁—NH—;orArg-Arg-γGlu-C(O)—CH₂—O—CH₂—CH₂—O—CH₂—CH₂—[NHC(O)—CH₂—O—CH₂—CH₂—O—CH₂—CH₂—]₁—NH—.

In some embodiments, n=1 and L is selected from the group consisting ofγGlu, γGlu-γGlu, γGlu-γGlu-γGlu, γGlu-γGlu-γGlu-γGlu, Glu, Glu-Glu,Glu-γGlu, Glu-Arg, Glu-Glu-Arg, His, His-His, His-γGlu, His-His-γGlu,Gly, Gly-γGlu, Ser, Ser-γGlu, D-Arg-D-Arg, Arg, Arg-Arg, Arg-Arg-γGlu,Ser-Ser, -Gly-Ser-Ser, Ser-Ser, -Gly-Ser-Ser-γGlu,Ser-Ser-Gly-Ser-Ser-Gly and Ser-Ser-Gly-Ser-Ser-Gly-γGlu, γGlu-OEG,γGlu-OEG-OEG and OEG.

In some embodiments, n=1 and L is selected from γGlu, γGlu-γGlu,γGlu-OEG, γGlu-OEG-OEG and OEG, more preferably the linker is γGlu-γGlu.

In another embodiment n=0; accordingly there is no linker between theamino acid residues of the polypeptide backbone and chemical moiety, Yi.e. Y is attached to an available position on the polypeptide backbone.

In one embodiment Y is an albumin binding moiety.

In one embodiment the albumin binding moiety is an acyl group.

Preferably the albumin binding moiety is HOOC(CH₂)_(s)CO—, wherein s isan integer from 12 to 22. More preferably s is an integer from 12 to 18.More preferably s is 16 to 18. More preferably s is 18.

In another embodiment the substituent group and/or group of formula(III) is selected from the following groups presented in Table 1.

TABLE 1 Abbreviation Substituent C20diacid

C20diacid-γGlu

C20diacid-γGlu-γGlu

C20diacid-γGlu-γGlu-γGlu

C20diacid-OEG

C20diacid-γGlu-OEG

C20diacid-γGlu-OEG-OEG

C18diacid-γGlu

C16diacid-γGlu

C14Diacid-γGlu

For embodiments that comprise an albumin binding moiety, thepolypeptides of the present invention can exhibit a protractedpharmacokinetic profile and good pharmacodynamic properties. Thereforethe polypeptides according to the present invention do not have to beinjected as often as known amylin products.

Further the polypeptides of the invention give a reduction in foodintake. The reduction in food intake is superior over the known amylinproduct (Pramlintide). Pram lintide reduces food intake by 25% aftersingle subcutaneous 1000 nmol/kg injection in rats. In comparison thepolypeptides according to the present invention trigger equivalentreductions in food intake in rats when administered in singlesubcutaneous doses considerable lower doses, which is demonstrated bydata anf figures throughout this patent application.

In one embodiment the albumin binding moiety binds non-covalently toalbumin. Preferably the albumin binding moiety has an albumin bindingaffinity towards human serum albumin that is below about 10 μM or belowabout 1 μM. In one embodiment the albumin binding moiety bindsnon-covalently to albumin. Preferably the albumin binding moiety has analbumin binding affinity towards human serum albumin that is below about10 μM. In one embodiment the albumin binding moiety binds non-covalentlyto albumin. Preferably the albumin binding moiety has an albumin bindingaffinity towards human serum albumin that is below about 1 μM. In oneembodiment the albumin binding moiety binds non-covalently to albumin.Preferably the albumin binding moiety has an albumin binding affinitytowards human serum albumin that is below about 10 μM to below about 1μM.

In one embodiment, the present invention concerns a polypeptidecomprising an amino acid sequence which is an analogue of SEQ ID No: 1wherein said analogue comprises a proline residue at position 21;wherein the amino acid sequence numbering of the analogue corresponds tothe amino acid numbering sequence of SEQ ID No: 1.

In one embodiment, the present invention concerns a which is an analogueof SEQ ID No: 1 wherein said analogue comprises a proline residue atposition 21; wherein the amino acid sequence numbering of the analoguecorresponds to the amino acid numbering sequence of SEQ ID No: 1. In oneembodiment, the present invention concerns a which is an analogue of SEQID No: 1 wherein said analogue comprises a proline residue at position21 and which optionally further comprises substitutions or deletionsrelative to SEQ ID No: 1; wherein the amino acid sequence numbering ofthe analogue corresponds to the amino acid numbering sequence of SEQ IDNo: 1.

In one embodiment, the present invention concerns a polypeptidecomprising an amino acid sequence which is an analogue of SEQ ID No: 1wherein said analogue comprises a proline residue at position 27;wherein the amino acid sequence numbering of the analogue corresponds tothe amino acid numbering sequence of SEQ ID No: 1. In one embodiment,the present invention concerns a which is an analogue of SEQ ID No: 1wherein said analogue comprises a proline residue at position 27;wherein the amino acid sequence numbering of the analogue corresponds tothe amino acid numbering sequence of SEQ ID No: 1. In one embodiment,the present invention concerns a which is an analogue of SEQ ID No: 1wherein said analogue comprises a proline residue at position 27 andwhich optionally further comprises substitutions or deletions relativeto SEQ ID No: 1; wherein the amino acid sequence numbering of theanalogue corresponds to the amino acid numbering sequence of SEQ ID No:1.

In one embodiment, the present invention concerns a polypeptidecomprising an amino acid sequence which is an analogue of SEQ ID No: 1wherein said analogue comprises a proline residue at position 21 and aproline residue at position 27; wherein the amino acid sequencenumbering of the analogue corresponds to the amino acid numberingsequence of SEQ ID No: 1. In one embodiment, the present inventionconcerns a which is an analogue of SEQ ID No: 1 wherein said analoguecomprises a proline residue at position 21 and a proline residue atposition 27; wherein the amino acid sequence numbering of the analoguecorresponds to the amino acid numbering sequence of SEQ ID No: 1. In oneembodiment, the present invention concerns a which is an analogue of SEQID No: 1 wherein said analogue comprises a proline residue at position21 and a proline residue at position 27 and which optionally furthercomprises substitutions or deletions relative to SEQ ID No: 1; whereinthe amino acid sequence numbering of the analogue corresponds to theamino acid numbering sequence of SEQ ID No: 1.

In one embodiment, the present invention concerns a polypeptidecomprising an amino acid sequence which is an analogue of SEQ ID No: 1wherein said analogue comprises a proline residue at position 21 and aproline residue at position 27 and an asparagine residue at position 14;wherein the amino acid sequence numbering of the analogue corresponds tothe amino acid numbering sequence of SEQ ID No: 1. In one embodiment,the present invention concerns a which is an analogue of SEQ ID No: 1wherein said analogue comprises a proline residue at position 21 and aproline residue at position 27 and an asparagine residue at position 14;wherein the amino acid sequence numbering of the analogue corresponds tothe amino acid numbering sequence of SEQ ID No: 1. In one embodiment,the present invention concerns a which is an analogue of SEQ ID No: 1wherein said analogue comprises a proline residue at position 21 and aproline residue at position 27 and an asparagine residue at position 14and which optionally further comprises substitutions or deletionsrelative to SEQ ID No: 1; wherein the amino acid sequence numbering ofthe analogue corresponds to the amino acid numbering sequence of SEQ IDNo: 1.

In one embodiment the polypeptide of the present invention comprises ananalogue of SEQ ID NO: 1, wherein said polypeptide has an IC₅₀ in ahuman amylin receptor binding assay of about 1200 pM or less;preferably, the polypeptide of the present invention consists of ananalogue of SEQ ID NO: 1 according to formula (I), as defined above,wherein said polypeptides have an IC₅₀ in a human amylin receptorbinding assay of about 1200 pM or less. In one embodiment thepolypeptide of the present invention is an analogue of SEQ ID NO: 1,wherein said polypeptide has an IC₅₀ in a human amylin receptor bindingassay of about 1200 pM or less; preferably, the polypeptide of thepresent invention is an analogue of SEQ ID NO: 1 according to formula(I), as defined above, wherein said polypeptides have an IC₅₀ in a humanamylin receptor binding assay of about 1200 pM or less. In oneembodiment the polypeptide of the present invention is an analogue ofSEQ ID NO: 1 optionally further comprising substitutions or deletionrelative to SEQ ID NO: 1, wherein said polypeptide has an IC₅₀ in ahuman amylin receptor binding assay of about 1200 pM or less;preferably, the polypeptide of the present invention is an analogue ofSEQ ID NO: 1 according to formula (I), as defined above, wherein saidpolypeptides have an IC₅₀ in a human amylin receptor binding assay ofabout 1200 pM or less. A suitable human amylin receptor binding assay todetermine the IC₅₀ is presented herein.

In one embodiment the polypeptide of the present invention consists ofan analogue of SEQ ID NO: 1, wherein said polypeptide has an IC₅₀ in ahuman amylin receptor binding assay of about 1200 pM or less;preferably, the polypeptide of the present invention consists of ananalogue of SEQ ID NO: 1 according to formula (I), as defined above,wherein said polypeptides have an IC₅₀ in a human amylin receptorbinding assay of about 1200 pM or less. A suitable human amylin receptorbinding assay to determine the IC₅₀ is presented herein.

Preferably the polypeptide of the present invention has a solubility ofat least 100 μM at pH 4 and a solubility of at least 100 μM at pH 7.5.

In one embodiment the polypeptide of the present invention is selectedfrom the following compounds presented in Table 2 (below). Table 2presents a list of compounds that have a hAmylinR IC50 value of lessthan 1200 pM. Further details regarding the compounds, such as IUPACnomenclature, may be found in Table 14.

TABLE 2 Albumin binding Example No. Sequence modifications moiety LinkerAcylation sites 1 14D, 17R, 21P, 26P, 35D C20 diacid 2xgGlu 1K 2 14D,17R, 21P, 27P, 35D C20 diacid 2xgGlu 1K 3 14D, 17R, 22P, 26P, 35D C20diacid 2xgGlu 1K 4 14E, 17R, 21P, 25P, 28P, 29P, 37P C20 diacid gGluN-terminal 5 14E, 17R, 21P, 26P, 37P C20 diacid gGlu N-terminal 6 14E,17R, 21P, 25P, 28P, 29P C20 diacid gGlu N-terminal 7 14E, 17R, 21P, 26PC20 diacid gGlu N-terminal 8 14E, 17R, 21P, 27P, 37P C20 diacid gGluN-terminal 9 14E, 17R, 21P, 27P C20 diacid gGlu N-terminal 10 14D, 17R,21P, 27P, 37P C20 diacid gGlu N-terminal 11 14E, 17R, 21P, 27P, 35D, 37PC20 diacid gGlu N-terminal 12 14E, 17R, 21P, 27P, 37P C20 diacid gGlu 1K13 14E, 17R, 21P, 27P, 37P C20 diacid 2xgGlu 1K 14 14E, 17R, 21P, 27P,37P C20 diacid 2xgGlu N-terminal 15 14E, 17R, 21P, 27P C20 diacid 2xgGluN-terminal 16 14E, 17R, 21P, 27P, 35R C20 diacid gGlu N-terminal 17 14E,17R, 21P, 27P, 34H C20 diacid gGlu N-terminal 18 14E, 17R, 21P, 27P, 35HC20 diacid gGlu N-terminal 19 14E, 17R, 21P, 27P C20 diacid gGlu-N-terminal 2xOEG 20 14E, 17R, 21P, 27P, 37P C20 diacid gGlu- N-terminal2xOEG 21 17R, 21P, 27P C20 diacid gGlu N-terminal 22 14E, 17R, 21P, 27P,35E C20 diacid gGlu N-terminal 23 17R, 21P, 27P, 35E C20 diacid gGluN-terminal 24 17R, 21P, 27P C20 diacid gGlu- N-terminal 2xOEG 25 17R,21P, 27P, 35E C20 diacid gGlu- 1K 2xOEG 26 17R, 21P, 27P, 35E C20 diacidgGlu- 1K OEG 27 17R, 21P, 27P, 35E C20 diacid gGlu 1K 28 17R, 21P, 27P,31P, 35E C20 diacid gGlu N-terminal 29 17R, 21P, 27P, 34P, 35E C20diacid gGlu N-terminal 30 14H, 17R, 21P, 27P, 35E C20 diacid gGluN-terminal 31 14E, 17R, 21P, 27P, 31P C20 diacid gGlu N-terminal 32 14E,17R, 21P, 27P, 34P C20 diacid gGlu N-terminal 33 14E, 17R, 21P, 28P, 35EC20 diacid gGlu N-terminal 34 17R, 21P, 27P, 35K C20 diacid gGluN-terminal 35 17R, 21P, 27P, 35K C20 diacid gGlu 1K 36 14E, 17R, 21P,27P, 34K C20 diacid gGlu N-terminal 37 14E, 17R, 21P, 27P, 29P C20diacid gGlu N-terminal 38 17R, 21P, 27P, 35R C20 diacid gGlu- 1K OEG 3917R, 21P, 27P, 34R C20 diacid gGlu N-terminal 40 17R, 21P, 27P, 34H C20diacid gGlu N-terminal 41 17R, 21P, 27P C20 diacid gGlu- 1K OEG 42 17R,21P, 27P C20 diacid none 1K 43 17R, 21P, 27P C20 diacid OEG 1K 44 −1K,1R, 17R, 21P, 27P, 35H C20 diacid gGlu −1K 45 −1K, 1R, 17R, 21P, 27P,35H C20 diacid gGlu- −1K OEG 46 −1G, 1R, 17R, 21P, 27P C20 diacid gGluN-terminal 47 −1G, 1R, 17R, 21P, 27P, 35H C20 diacid gGlu N-terminal 4817R, 21P, 27P C20 diacid gGlu 1K 49 17R, 21P, 27P, 31P C20 diacid gGlu-1K OEG 50 17R, 21P, 27P, 34P C20 diacid gGlu- 1K OEG 51 14E, 17R, 21P,27P, 35R C20 diacid gGlu 1K 52 14D, 17R, 21P, 27P, 35R C20 diacid 2xgGlu1K 53 17R, 21P, 27P, 28P, 31P C20 diacid gGlu- 1K OEG 54 17R, 21P, 27P,29P, 31P C20 diacid gGlu- 1K OEG 55 17R, 21P, 27P, 28P, 34P C20 diacidgGlu- 1K OEG 56 17R, 21P, 27P, 29P, 34P C20 diacid gGlu- 1K OEG 57 17R,21P, 27P, 31P, 35H C20 diacid gGlu- 1K OEG 58 17R, 21P, 27P, 34P, 35HC20 diacid gGlu- 1K OEG 59 14D, 17R, 21K, 27P, 35D C20 diacid 2xgGlu 21K60 17R, 21P, 27P, 35H C20 diacid gGlu 1K 61 14H, 17R, 21P, 27P, 31P C20diacid gGlu- 1K OEG 62 14H, 17R, 21P, 27P, 31P C20 diacid gGlu 1K 6314R, 17R, 21P, 27P, 31P C20 diacid gGlu 1K 64 14R, 17R, 21P, 27P, 31PC20 diacid gGlu- 1K OEG 65 14R, 17R, 21P, 27P, 34P C20 diacid gGlu 1K 6614H, 17R, 21P, 27P, 35H C20 diacid gGlu 1K 67 14H, 17R, 21P, 27P, 34PC20 diacid gGlu 1K 68 14H, 17R, 21P, 27P, 34P C20 diacid gGlu- 1K OEG 6914H, 17R, 21P, 27P C20 diacid gGlu- 1K OEG 70 14H, 17R, 21P, 27P C20diacid gGlu 1K 71 14G, 17R, 21P, 27P, 31P C20 diacid gGlu- 1K OEG 7214A, 17R, 21P, 27P, 31P C20 diacid gGlu- 1K OEG 73 14S, 17R, 21P, 27P,31P C20 diacid gGlu- 1K OEG 74 14K, 17R, 21P, 27P, 31P C20 diacid gGlu-1K OEG 75 14T, 17R, 21P, 27P, 31P C20 diacid gGlu- 1K OEG 76 17R, 21P,27P, 34H C20 diacid gGlu- 1K OEG 77 17R, 21P, 27P, 34H C20 diacid gGlu1K 78 17R, 21P, 27P, 34R C20 diacid gGlu- 1K OEG 79 17R, 21P, 27P, 34RC20 diacid gGlu 1K 80 14H, 17R, 21P, 27P, 34H C20 diacid gGlu- 1K OEG 8114H, 17R, 21P, 27P, 34H C20 diacid gGlu 1K 82 14R, 17R, 21P, 27P C20diacid gGlu- 1K OEG 83 14R, 17R, 21P, 27P C20 diacid gGlu 1K 84 14H,17R, 21P, 27P, 34R C20 diacid gGlu- 1K OEG 85 14H, 17R, 21P, 27P, 34RC20 diacid gGlu 1K 86 17R, 21P, 27P, 34H C20 diacid 2xgGlu 1K 87 14E,17R, 21P, 27P, 34H C20 diacid 2xgGlu 1K 88 14E, 17R, 21P, 27P, 34R C20diacid 2xgGlu 1K 89 14E, 17R, 21P, 27P, 35R C20 diacid 2xgGlu 1K 90 14H,17R, 21P, 27P C20 diacid OEG 1K 91 17R, 21P, 27P, 34H C20 diacid OEG 1K92 14H, 17R, 21P, 27P C20 diacid 2xgGlu 1K 93 14A, 17R, 21P, 27P, 34HC20 diacid gGlu 1K 94 14A, 17R, 21P, 27P, 34P C20 diacid gGlu 1K 95 17R,21P, 27P, 34R C20 diacid gGlu- 1K 2xOEG 96 17R, 21P, 27P, 31P C20 diacidgGlu- 1K 2xOEG 97 17R, 21P, 27P, 34H C20 diacid gGlu- 1K 2xOEG 98 17R,21P, 27P, 34P C20 diacid gGlu- 1K 2xOEG 99 −1G, 1R, 14H, 17R, 21P, 27PC20 diacid gGlu N-terminal 100 −1G, 1R, 14H, 17R, 21P, 27P, 34H C20diacid gGlu N-terminal 101 −1G, 1R, 14A, 17R, 21P, 27P, 34H C20 diacidgGlu N-terminal 102 −1G, 1R, 14H, 17R, 21P, 27P, 34P C20 diacid gGluN-terminal 103 −1G, 1R, 14A, 17R, 21P, 27P, 34P C20 diacid gGluN-terminal 104 14E, 17R, 21P, 27P, 34H, 35E C20 diacid 2xgGlu 1K 10514E, 17R, 21P, 27P, 34R, 35E C20 diacid 2xgGlu 1K 106 14E, 17R, 21P,27P, 34P, 35E C20 diacid 2xgGlu 1K 107 14E, 17R, 21P, 27P, 34H, 35E C20diacid gGlu 1K 108 14E, 17R, 21P, 27P, 34R, 35E C20 diacid gGlu 1K 10914E, 17R, 21P, 27P, 34P, 35E C20 diacid gGlu 1K 110 14E, 17R, 21P, 27P,34P, 35R C20 diacid 2xgGlu 1K 111 17R, 21P, 27P, 34H C16 diacid gGlu 1K112 17R, 21P, 27P, 34H C14 diacid gGlu 1K 113 17R, 21P, 27P, 34H C18diacid gGlu 1K 114 14E, 17R, 21P, 27P, 34P, 37P C20 diacid gGlu 1K 11514H, 17R, 21P, 27P, 34P, 37P C20 diacid gGlu 1K 116 14H, 17R, 21P, 27P,31P, 34P C20 diacid gGlu 1K 117 14E, 17R, 21P, 27P, 34P, 35R C20 diacidgGlu 1K 118 14E, 17R, 21P, 27P, 34P, 35H C20 diacid gGlu 1K 119 17R,21P, 27P, 31P, 34P, 35R C20 diacid 2xgGlu 1K 120 14S, 17R, 21P, 27P,34P, 35E C20 diacid 2xgGlu 1K 121 14E, 17R, 21P, 31P, 34P, 35E C20diacid 2xgGlu 1K 122 14D, 17R, 21P, 27P, 34P, 35E C20 diacid 2xgGlu 1K123 14D, 17R, 21P, 27P, 34P, 35E C20 diacid gGlu 1K 124 14E, 17R, 21P,27P, 34P, 35H C20 diacid 2xgGlu 1K 125 14E, 17R, 21P, 27P, 34P, 35E, 37PC20 diacid 2xgGlu 1K 126 14E, 17R, 23P, 34P, 35E C20 diacid 2xgGlu 1K127 14E, 17R, 21P, 27P, 34P, 37F C20 diacid 2xgGlu 1K 128 14E, 17R, 21P,27P, 35H C20 diacid gGlu 1K 129 14D, 17R, 21P, 27P, 34P, 35R C20 diacidgGlu 1K 130 14D, 17R, 21P, 27P, 34P, 35R C20 diacid 2xgGlu 1K 131 14d,17R, 21P, 27P, 35R C20 diacid 2xgGlu 1K 132 14D, 17R, 21P, 27P, 35R nonenone

In a further embodiment the polypeptide of the present invention isselected from the following compounds presented in Table 3 (below).

Table 3 presents compounds that have a hAmylinR IC50 value of less than1200 pM and a ratio of hCT/hAmylin binding of at least 10. Furtherdetails regarding the compounds, such as IUPAC nomenclature, may befound in Table 14.

TABLE 3 Albumin binding Acylation Example no. Sequence modificationsmoiety Linker sites 1 14D, 17R, 21P, 26P, 35D C20 diacid 2xgGlu 1K 214D, 17R, 21P, 27P, 35D C20 diacid 2xgGlu 1K 3 14D, 17R, 22P, 26P, 35DC20 diacid 2xgGlu 1K 6 14E, 17R, 21P, 25P, 28P, 29P C20 diacid gGluN-terminal 7 14E, 17R, 21P, 26P C20 diacid gGlu N-terminal 15 14E, 17R,21P, 27P C20 diacid 2xgGlu N-terminal 16 14E, 17R, 21P, 27P, 35R C20diacid gGlu N-terminal 17 14E, 17R, 21P, 27P, 34H C20 diacid gGluN-terminal 19 14E, 17R, 21P, 27P C20 diacid gGlu- N-terminal 2xOEG 2117R, 21P, 27P C20 diacid gGlu N-terminal 22 14E, 17R, 21P, 27P, 35E C20diacid gGlu N-terminal 23 17R, 21P, 27P, 35E C20 diacid gGlu N-terminal24 17R, 21P, 27P C20 diacid gGlu- N-terminal 2xOEG 25 17R, 21P, 27P, 35EC20 diacid gGlu- 1K 2xOEG 26 17R, 21P, 27P, 35E C20 diacid gGlu- 1K OEG27 17R, 21P, 27P, 35E C20 diacid gGlu 1K 28 17R, 21P, 27P, 31P, 35E C20diacid gGlu N-terminal 29 17R, 21P, 27P, 34P, 35E C20 diacid gGluN-terminal 30 14H, 17R, 21P, 27P, 35E C20 diacid gGlu N-terminal 31 14E,17R, 21P, 27P, 31P C20 diacid gGlu N-terminal 32 14E, 17R, 21P, 27P, 34PC20 diacid gGlu N-terminal 34 17R, 21P, 27P, 35K C20 diacid gGluN-terminal 35 17R, 21P, 27P, 35K C20 diacid gGlu 1K 36 14E, 17R, 21P,27P, 34K C20 diacid gGlu N-terminal 38 17R, 21P, 27P, 35R C20 diacidgGlu- 1K OEG 39 17R, 21P, 27P, 34R C20 diacid gGlu N-terminal 40 17R,21P, 27P, 34H C20 diacid gGlu N-terminal 41 17R, 21P, 27P C20 diacidgGlu- 1K OEG 42 17R, 21P, 27P C20 diacid none 1K 43 17R, 21P, 27P C20diacid OEG 1K 44 −1K, 1R, 17R, 21P, 27P, 35H C20 diacid gGlu −1K 45 −1K,1R, 17R, 21P, 27P, 35H C20 diacid gGlu- −1K OEG 46 −1G, 1R, 17R, 21P,27P C20 diacid gGlu N-terminal 47 −1G, 1R, 17R, 21P, 27P, 35H C20 diacidgGlu N-terminal 48 17R, 21P, 27P C20 diacid gGlu 1K 49 17R, 21P, 27P,31P C20 diacid gGlu- 1K OEG 50 17R, 21P, 27P, 34P C20 diacid gGlu- 1KOEG 51 14E, 17R, 21P, 27P, 35R C20 diacid gGlu 1K 52 14D, 17R, 21P, 27P,35R C20 diacid 2xgGlu 1K 53 17R, 21P, 27P, 28P, 31P C20 diacid gGlu- 1KOEG 54 17R, 21P, 27P, 29P, 31P C20 diacid gGlu- 1K OEG 55 17R, 21P, 27P,28P, 34P C20 diacid gGlu- 1K OEG 56 17R, 21P, 27P, 29P, 34P C20 diacidgGlu- 1K OEG 57 17R, 21P, 27P, 31P, 35H C20 diacid gGlu- 1K OEG 58 17R,21P, 27P, 34P, 35H C20 diacid gGlu- 1K OEG 60 17R, 21P, 27P, 35H C20diacid gGlu 1K 61 14H, 17R, 21P, 27P, 31P C20 diacid gGlu- 1K OEG 6214H, 17R, 21P, 27P, 31P C20 diacid gGlu 1K 63 14R, 17R, 21P, 27P, 31PC20 diacid gGlu 1K 64 14R, 17R, 21P, 27P, 31P C20 diacid gGlu- 1K OEG 6514R, 17R, 21P, 27P, 34P C20 diacid gGlu 1K 66 14H, 17R, 21P, 27P, 35HC20 diacid gGlu 1K 67 14H, 17R, 21P, 27P, 34P C20 diacid gGlu 1K 68 14H,17R, 21P, 27P, 34P C20 diacid gGlu- 1K OEG 69 14H, 17R, 21P, 27P C20diacid gGlu- 1K OEG 70 14H, 17R, 21P, 27P C20 diacid gGlu 1K 71 14G,17R, 21P, 27P, 31P C20 diacid gGlu- 1K OEG 72 14A, 17R, 21P, 27P, 31PC20 diacid gGlu- 1K OEG 73 14S, 17R, 21P, 27P, 31P C20 diacid gGlu- 1KOEG 74 14K, 17R, 21P, 27P, 31P C20 diacid gGlu- 1K OEG 75 14T, 17R, 21P,27P, 31P C20 diacid gGlu- 1K OEG 76 17R, 21P, 27P, 34H C20 diacid gGlu-1K OEG 77 17R, 21P, 27P, 34H C20 diacid gGlu 1K 78 17R, 21P, 27P, 34RC20 diacid gGlu- 1K OEG 79 17R, 21P, 27P, 34R C20 diacid gGlu 1K 80 14H,17R, 21P, 27P, 34H C20 diacid gGlu- 1K OEG 81 14H, 17R, 21P, 27P, 34HC20 diacid gGlu 1K 82 14R, 17R, 21P, 27P C20 diacid gGlu- 1K OEG 83 14R,17R, 21P, 27P C20 diacid gGlu 1K 84 14H, 17R, 21P, 27P, 34R C20 diacidgGlu- 1K OEG 85 14H, 17R, 21P, 27P, 34R C20 diacid gGlu 1K 86 17R, 21P,27P, 34H C20 diacid 2xgGlu 1K 87 14E, 17R, 21P, 27P, 34H C20 diacid2xgGlu 1K 88 14E, 17R, 21P, 27P, 34R C20 diacid 2xgGlu 1K 89 14E, 17R,21P, 27P, 35R C20 diacid 2xgGlu 1K 90 14H, 17R, 21P, 27P C20 diacid OEG1K 91 17R, 21P, 27P, 34H C20 diacid OEG 1K 92 14H, 17R, 21P, 27P C20diacid 2xgGlu 1K 93 14A, 17R, 21P, 27P, 34H C20 diacid gGlu 1K 94 14A,17R, 21P, 27P, 34P C20 diacid gGlu 1K 95 17R, 21P, 27P, 34R C20 diacidgGlu- 1K 2xOEG 96 17R, 21P, 27P, 31P C20 diacid gGlu- 1K 2xOEG 97 17R,21P, 27P, 34H C20 diacid gGlu- 1K 2xOEG 98 17R, 21P, 27P, 34P C20 diacidgGlu- 1K 2xOEG 99 −1G, 1R, 14H, 17R, 21P, 27P C20 diacid gGlu N-terminal100 −1G, 1R, 14H, 17R, 21P, 27P, 34H C20 diacid gGlu N-terminal 101 −1G,1R, 14A, 17R, 21P, 27P, 34H C20 diacid gGlu N-terminal 102 −1G, 1R, 14H,17R, 21P, 27P, 34P C20 diacid gGlu N-terminal 103 −1G, 1R, 14A, 17R,21P, 27P, 34P C20 diacid gGlu N-terminal 104 14E, 17R, 21P, 27P, 34H,35E C20 diacid 2xgGlu 1K 105 14E, 17R, 21P, 27P, 34R, 35E C20 diacid2xgGlu 1K 106 14E, 17R, 21P, 27P, 34P, 35E C20 diacid 2xgGlu 1K 107 14E,17R, 21P, 27P, 34H, 35E C20 diacid gGlu 1K 108 14E, 17R, 21P, 27P, 34R,35E C20 diacid gGlu 1K 109 14E, 17R, 21P, 27P, 34P, 35E C20 diacid gGlu1K 110 14E, 17R, 21P, 27P, 34P, 35R C20 diacid 2xgGlu 1K 111 17R, 21P,27P, 34H C16 diacid gGlu 1K 112 17R, 21P, 27P, 34H C14 diacid gGlu 1K113 17R, 21P, 27P, 34H C18 diacid gGlu 1K 116 14H, 17R, 21P, 27P, 31P,34P C20 diacid gGlu 1K 117 14E, 17R, 21P, 27P, 34P, 35R C20 diacid gGlu1K 118 14E, 17R, 21P, 27P, 34P, 35H C20 diacid gGlu 1K 119 17R, 21P,27P, 31P, 34P, 35R C20 diacid 2xgGlu 1K 120 14S, 17R, 21P, 27P, 34P, 35EC20 diacid 2xgGlu 1K 121 14E, 17R, 21P, 31P, 34P, 35E C20 diacid 2xgGlu1K 122 14D, 17R, 21P, 27P, 34P, 35E C20 diacid 2xgGlu 1K 123 14D, 17R,21P, 27P, 34P, 35E C20 diacid gGlu 1K 124 14E, 17R, 21P, 27P, 34P, 35HC20 diacid 2xgGlu 1K 127 14E, 17R, 21P, 27P, 34P, 37F C20 diacid 2xgGlu1K 128 14E, 17R, 21P, 27P, 35H C20 diacid gGlu 1K 129 14D, 17R, 21P,27P, 34P, 35R C20 diacid gGlu 1K 130 14D, 17R, 21P, 27P, 34P, 35R C20diacid 2xgGlu 1K 131 14d, 17R, 21P, 27P, 35R C20 diacid 2xgGlu 1K 13214D, 17R, 21P, 27P, 35R none none

In this Table of compounds the term “sequence modifications” meansmodifications with respect to human amylin.

The polypeptides of the present invention may inhibit food intake,inhibit gastric emptying and glucagon secretion or other physiologicaleffects as is known in the art.

The polypeptides of the present invention retain amylin binding. Amylinbinding refers to the ability to bind to the amylin receptor,specifically to have an IC₅₀ of about 1200 pM or less in a human amylinbinding assay. For example, the polypeptides of the invention can betested for amylin binding using the Assay presented herein.

As demonstrated in the Examples section herein, the polypeptidespresented above have an IC₅₀ in a human amylin receptor binding assay ofabout 1200 pM or less.

In one embodiment, the polypeptides of the present invention have anIC₅₀ of about 1200 pM (picomolar) or less in a human binding assay. Inone embodiment, the polypeptides of the present invention have an IC₅₀of 1100 pM or less in a human binding assay. In one embodiment, thepolypeptides of the present invention have an IC₅₀ of 1000 pM or less ina human binding assay. In one embodiment, the polypeptides of thepresent invention have an IC₅₀ of 900 pM or less in a human bindingassay. In one embodiment, the polypeptides of the present invention havean IC₅₀ of 800 pM or less in a human binding assay. In one embodiment,the polypeptides of the present invention have an IC₅₀ of 750 pM or lessin a human binding assay. In one embodiment, the polypeptides of thepresent invention have an IC₅₀ of 700 pM or less in a human bindingassay.

In one embodiment, the IC₅₀ is measured in a human binding Assaypresented herein.

In one embodiment, the polypeptides of the present invention may exhibitselectivity for amylin receptors over calcitonin receptors. In oneembodiment, the polypeptides of the present invention may exhibitselectivity for human amylin receptors over human calcitonin receptors.

For example, selectivity may be assessed by measuring the IC₅₀ in anamylin binding assay—such as that presented herein (e.g. Assay (V))—andmeasuring the IC₅₀ in a calcitonin binding assay—such as that presentedherein (e.g. Assay (VII)) and then calculating the ratio of the two IC₅₀values according to the equation below:

Selectivity=IC ₅₀ in the calcitonin binding assay/IC ₅₀ in the amylinbinding assay

In one embodiment, the polypeptides of the invention are more selectivein amylin potency or binding assays than in calcitonin potency orbinding assays.

The calcitonin and amylin binding or potency assays may use receptorsfrom any species provided like is compared with like. The binding orpotency assays may both use rat receptors or may both use humanreceptors, or combinations thereof. An example of a suitable humanbinding assay is presented herein. An example of a suitable humanpotency assay is presented herein. An example of a suitable rat bindingassay is presented herein. An example of a suitable rat potency assay ispresented herein.

In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 5 when both binding assays use human receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 10 when both binding assays use human receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 20 when both binding assays use human receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 30 when both binding assays use human receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 40 when both binding assays use human receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 50 when both binding assays use human receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 60 when both binding assays use human receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 70 when both binding assays use human receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 80 when both binding assays use human receptors.

In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 10 when both binding assays use rat receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 20 when both binding assays use rat receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 30 when both binding assays use rat receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 40 when both binding assays use rat receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 50 when both binding assays use rat receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 60 when both binding assays use rat receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 70 when both binding assays use rat receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 80 when both binding assays use rat receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 100 when both binding assays use rat receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 150 when both binding assays use rat receptors.

In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 200 when both binding assays use rat receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 300 when both binding assays use rat receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 400 when both binding assays use rat receptors.In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 450 when both binding assays use rat receptors.

In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 5 when both potency assays use human receptors.

In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 10 when both potency assays use human receptors.

In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 20 when both potency assays use human receptors.

In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 30 when both potency assays use human receptors.

In one embodiment, the polypeptides of the invention have a selectivityvalue of about at least 40 when both potency assays use human receptors.

For some embodiments, the polypeptide of the present invention has aprotracted pharmacokinetic profile compared to pramlintide as measuredby the Assay described herein.

For some embodiments, the polypeptide of the present invention has aplasma T½ of at least 30 hours. For some embodiments, the polypeptide ofthe present invention has a plasma T½ of at least 40 hours. For someembodiments, the polypeptide of the present invention has a plasma T½ ofat least 50 hours. For some embodiments, the polypeptide of the presentinvention has a plasma T½ of at least 60 hours. For some embodiments,the polypeptide of the present invention has a plasma T½ of at least 70hours. For some embodiments, the polypeptide of the present inventionhas a plasma T½ of at least 75 hours. For some embodiments, thepolypeptide of the present invention has a plasma T½ of at least 80hours. For some embodiments, the polypeptide of the present inventionhas a plasma T½ of at least 85 hours. For some embodiments, thepolypeptide of the present invention has a plasma T½ of at least 90hours. For some embodiments, the polypeptide of the present inventionhas a plasma T½ of at least 95 hours. For some embodiments, thepolypeptide of the present invention has a plasma T½ of at least 100hours.

Process

The production of polypeptides such as amylin or analogues thereof iswell known in the art.

The polypeptides of the invention can thus be produced by classicalpolypeptide synthesis, e.g. solid phase polypeptide synthesis usingt-Boc or Fmoc chemistry or other well established techniques, see e.g.Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley &Sons, 1999. The polypeptides may also be produced by a method whichcomprises culturing a host cell containing a DNA sequence encoding thepolypeptide and capable of expressing the polypeptide in a suitablenutrient medium under conditions permitting the expression of thepolypeptide. For polypeptides comprising non-natural amino acidresidues, the recombinant cell should be modified such that thenon-natural amino acids are incorporated into the polypeptide, forinstance by use of tRNA mutants.

Pharmaceutical Compositions

In one embodiment the invention concerns a pharmaceutical compositioncomprising a polypeptide according of the invention, and apharmaceutically acceptable excipient. The compositions are suited forparenteral administration.

In one embodiment the polypeptide is present in the formulation at aconcentration of from about 0.1 mg/ml to about 25 mg/ml. In anotherembodiment, the polypeptide is present in the formulation at aconcentration of from about 1 mg/ml to about 10 mg/ml.

In another embodiment, the formulation has a pH from 2.0 to 10.0. Inanother embodiment, the formulation has a pH from 2.0 to 7.0. In anotherembodiment, the formulation has a pH from 2.5 to 4.5. In anotherembodiment, the formulation has a pH from 3.5 to 4.5.

Pharmaceutical compositions containing a polypeptide according to thepresent invention may be prepared by conventional techniques, e.g. asdescribed in Remington's Pharmaceutical Sciences, 1985 or in Remington:The Science and Practice of Pharmacy, 19^(th) edition, 1995.

The formulation may further comprise a buffer system, preservative(s),isotonicity agent(s), chelating agent(s), stabilizers and/orsurfactants. The use of such excipients in pharmaceutical compositionsis well-known to the skilled person. For convenience reference is madeto Remington: The Science and Practice of Pharmacy, 19^(th) edition,1995.

In one embodiment the pharmaceutical formulation is an aqueousformulation, i.e. formulation comprising water. Such formulation istypically a solution or a suspension. In a further embodiment of theinvention the pharmaceutical formulation is an aqueous solution.

The term “aqueous formulation” is defined as a formulation comprising atleast 50% w/w water.

Likewise, the term “aqueous solution” is defined as a solutioncomprising at least 50% w/w water, and the term “aqueous suspension” isdefined as a suspension comprising at least 50% w/w water.

In another embodiment the pharmaceutical formulation is a freeze-driedformulation, whereto the physician or the patient adds solvents and/ordiluents prior to use. In another embodiment the pharmaceuticalformulation is a dried formulation (e.g. freeze-dried or spray-dried)ready for use without any prior dissolution.

By “dried form” is intended the liquid pharmaceutical composition orformulation is dried either by freeze drying (i.e., lyophilization; see,for example, Williams and Polli (1984) J. Parenteral Sci. Technol.38:48-59), spray drying (see Masters (1991) in Spray-Drying Handbook(5th ed; Longman Scientific and Technical, Essez, U.K.), pp. 491-676;Broadhead et al. (1992) Drug Devel. Ind. Pharm. 18:1169-1206; andMumenthaler et al. (1994) Pharm. Res. 11:12-20), or air drying(Carpenter and Crowe (1988) Cryobiology 25:459-470; and Roser (1991)Biopharm. 4:47-53).

In a further embodiment of the invention the buffer is selected from thegroup consisting of acetate, carbonate, citrate, glycylglycine,histidine, glycine, lysine, arginine, dihydrogen phosphate, hydrogenphosphate, phosphate, and tris(hydroxymethyl)-aminomethan, bicine,tricine, malic acid, lactic acid, succinate, maleic acid, fumaric acid,tartaric acid, aspartic acid or mixtures thereof. Each one of thesespecific buffers constitutes an alternative embodiment of the invention.

In another embodiment of the invention the formulation further comprisesa pharmaceutically acceptable preservative. In a further embodiment ofthe invention the formulation further comprises an isotonic agent, e.g.propylene glycol, mannitol or glycerol. In a further embodiment of theinvention the formulation further comprises a chelating agent.

In another embodiment of the invention the formulation further comprisesa stabilizer. The use of a stabilizer in pharmaceutical compositions iswell-known to the skilled person. For convenience reference is made toRemington: The Science and Practice of Pharmacy, 19^(th) edition, 1995.

Aggregate formation by a polypeptide during storage of a liquidpharmaceutical composition can adversely affect biological activity ofthat polypeptide, resulting in loss of therapeutic efficacy of thepharmaceutical composition. Furthermore, aggregate formation may causeother problems such as blockage of tubing, membranes, or pumps when thepolypeptide-containing pharmaceutical composition is administered usingan infusion system.

Compositions of the invention are stabilized liquid pharmaceuticalcompositions whose therapeutically active components include apolypeptide that possibly exhibits aggregate formation during storage inliquid pharmaceutical formulations.

By “aggregate formation” is intended a physical interaction between thepolypeptide molecules that results in formation of oligomers, which mayremain soluble, or large visible aggregates that precipitate from thesolution.

By “during storage” is intended a liquid pharmaceutical composition orformulation once prepared, is not immediately administered to a subject.Rather, following preparation, it is packaged for storage, either in aliquid form, in a frozen state, or in a dried form for laterreconstitution into a liquid form or other form suitable foradministration to a subject.

The pharmaceutical compositions of the invention may further comprise anamount of an amino acid base sufficient to decrease aggregate formationby the polypeptide during storage of the composition.

By “amino acid base” is intended an amino acid or a combination of aminoacids, where any given amino acid is present either in its free baseform or in its salt form. Where a combination of amino acids is used,all of the amino acids may be present in their free base forms, all maybe present in their salt forms, or some may be present in their freebase forms while others are present in their salt forms. In oneembodiment, amino acids used in preparing the compositions of theinvention are those carrying a charged side chain, such as arginine,lysine, aspartic acid, and glutamic acid. Any stereoisomer (i.e., L, D,or a mixture thereof) of a particular amino acid (e.g. methionine,histidine, imidazole, arginine, lysine, isoleucine, aspartic acid,tryptophan, threonine and mixtures thereof) or combinations of thesestereoisomers, may be present in the pharmaceutical compositions of theinvention so long as the particular amino acid is present either in itsfree base form or its salt form. In one embodiment the L-stereoisomer isused. Compositions of the invention may also be formulated withderivatives of these amino acids. Suitable arginine derivatives include,for example, aminoguanidine, ornithine and N-monoethyl L-arginine,suitable methionine derivatives include ethionine and buthionine andsuitable cysteine derivatives include S-methyl-L cysteine. As with theother amino acids, the amino acid derivatives are incorporated into thecompositions in either their free base form or their salt form. In aanother embodiment of the invention the amino acids or amino acidderivatives thereof are used in a concentration, which is sufficient toprevent or delay aggregation of the protein.

In another embodiment of the invention the formulation further comprisesa surfactant. In another embodiment of the invention the formulationfurther comprises protease inhibitors. The use of a protease inhibitoris particular useful in pharmaceutical compositions comprising zymogensof proteases in order to inhibit autocatalysis.

It is possible that other ingredients may be present in the polypeptidepharmaceutical formulation of the present invention. Such additionalingredients may include wetting agents, emulsifiers, antioxidants,bulking agents, tonicity modifiers, chelating agents, metal ions,oleaginous vehicles, proteins (e.g., human serum albumin, gelatine orproteins) and a zwitterion (e.g., an amino acid such as betaine,taurine, arginine, glycine, lysine and histidine). Such additionalingredients, of course, should not adversely affect the overallstability of the pharmaceutical formulation of the present invention.

Pharmaceutical compositions containing a polypeptide according to thepresent invention may be administered to a patient in need of suchtreatment at several sites, for example, at topical sites, for example,skin and mucosal sites, at sites which bypass absorption, for example,administration in an artery, in a vein, in the heart, and at sites whichinvolve absorption, for example, administration in the skin, under theskin, in a muscle or in the abdomen.

Administration of pharmaceutical compositions according to the inventionmay be through several routes of administration, for example, lingual,sublingual, buccal, in the mouth, oral, in the stomach and intestine,nasal, pulmonary, for example, through the bronchioles and alveoli or acombination thereof, epidermal, dermal, transdermal, vaginal, rectal,ocular, for examples through the conjunctiva, uretal, and parenteral topatients in need of such a treatment.

Compositions of the current invention may be administered in severaldosage forms, for example, as solutions, suspensions, emulsions,microemulsions, multiple emulsion, foams, salves, pastes, plasters,ointments, tablets, coated tablets, rinses, capsules, for example, hardgelatine capsules and soft gelatine capsules, suppositories, rectalcapsules, drops, gels, sprays, powder, aerosols, inhalants, eye drops,ophthalmic ointments, ophthalmic rinses, vaginal pessaries, vaginalrings, vaginal ointments, injection solution, in situ transformingsolutions, for example in situ gelling, in situ setting, in situprecipitating, in situ crystallization, infusion solution, and implants.

Compositions of the invention may further be compounded in, or attachedto, for example through covalent, hydrophobic and electrostaticinteractions, a drug carrier, drug delivery system and advanced drugdelivery system in order to further enhance stability of the derivativeof an amylin analogue thereof increase bioavailability, increasesolubility, decrease adverse effects, achieve chronotherapy well knownto those skilled in the art, and increase patient compliance or anycombination thereof.

Compositions of the current invention are useful in the formulation ofsolids, semisolids, powder and solutions for pulmonary administration ofthe derivative of an amylin analogue, using, for example a metered doseinhaler, dry powder inhaler and a nebulizer, all being devices wellknown to those skilled in the art.

Compositions of the current invention are useful in the formulation ofcontrolled, sustained, protracting, retarded, and slow release drugdelivery systems.

Parenteral administration may be performed by subcutaneous,intramuscular, intraperitoneal or intravenous injection by means of asyringe, optionally a pen-like syringe. Alternatively, parenteraladministration can be performed by means of an infusion pump. A furtheroption is a composition which may be a solution or suspension for theadministration of the derivative of an amylin analogue in the form of anasal or pulmonal spray. As a still further option, the pharmaceuticalcompositions containing the polypeptide of the invention can also beadapted to transdermal administration, e.g. by needle-free injection orfrom a patch, optionally an iontophoretic patch, or transmucosal, e.g.buccal, administration.

The polypeptide of the invention can be administered via the pulmonaryroute in a vehicle, as a solution, suspension or dry powder using any ofknown types of devices suitable for pulmonary drug delivery. Examples ofthese comprise of, but are not limited to, the three general types ofaerosol-generating for pulmonary drug delivery, and may include jet orultrasonic nebulizers, metered-dose inhalers, or dry powder inhalers(cf. Yu J, Chien Y W. ulmonary drug delivery: Physiologic andmechanistic embodiments. Crit. Rev Ther Drug Carr Sys 14(4) (1997)395-453).

In one embodiment of the invention the pharmaceutical formulationcomprising the polypeptide of the invention is stable for more than 6weeks of usage and for more than 3 years of storage.

In another embodiment of the invention the pharmaceutical formulationcomprising the polypeptide of the invention is stable for more than 4weeks of usage and for more than 3 years of storage.

In another embodiment of the invention the pharmaceutical formulationcomprising the derivative of an amylin analogue is stable for more than4 weeks of usage and for more than two years of storage.

In another embodiment of the invention the pharmaceutical formulationcomprising the derivative of an amylin analogue is stable for more than2 weeks of usage and for more than two years of storage.

In one embodiment a process for preparing a pharmaceutical compositioncomprising the derivative according to the invention comprises mixing aderivative according to the invention with at least one pharmaceuticallyacceptable excipient.

Therapeutic Indications

In one embodiment the derivative according to the invention can be usedas a medicament. In one embodiment the amylin derivative according tothe invention can be used as a medicament. In one embodiment the amylinpeptide according to the invention can be used as a medicament.

In one embodiment the derivative can be used as a medicament for thetreatment or prevention of hyperglycemia, type 2 diabetes, impairedglucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X,dyslipidemia, cognitive disorders, atherosclerosis, myocardialinfarction, coronary heart disease and other cardiovascular disorders,stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers. Inone embodiment the amylin derivative according to the invention can beused as a medicament for the treatment or prevention of hyperglycemia,type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity,hypertension, syndrome X, dyslipidemia, cognitive disorders,atherosclerosis, myocardial infarction, coronary heart disease and othercardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsiaand gastric ulcers. In one embodiment the amylin peptide according tothe invention can be used as a medicament for the treatment orprevention of hyperglycemia, type 2 diabetes, impaired glucosetolerance, type 1 diabetes, obesity, hypertension, syndrome X,dyslipidemia, cognitive disorders, atherosclerosis, myocardialinfarction, coronary heart disease and other cardiovascular disorders,stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers.

In one embodiment the medicament for delaying or preventing diseaseprogression in type 2 diabetes.

In one embodiment the derivative can be used as a medicament for thetreatment of or prevention of obesity. In one embodiment the amylinderivative according to the invention can be used as a medicament forthe treatment of or prevention of obesity. In one embodiment the amylinpeptide according to the invention can be used as a medicament for thetreatment of or prevention of obesity.

In one embodiment the derivative can be used as a medicament forreduction of food intake. In one embodiment the amylin derivativeaccording to the invention can be used as a medicament for reduction offood intake. In one embodiment the amylin peptide according to theinvention can be used as a medicament for reduction of food intake

In one embodiment the medicament can be used for decreasing food intake,decreasing β-cell apoptosis, increasing β-cell function and β-cell mass,and/or for restoring glucose sensitivity to β-cells.

In one embodiment the polypeptide according to the invention can be usedfor the preparation of a medicament.

In one embodiment the derivative can be used for the preparation of amedicament for the treatment or prevention of hyperglycemia, type 2diabetes, impaired glucose tolerance, type 1 diabetes, obesity,hypertension, syndrome X, dyslipidemia, cognitive disorders,atherosclerosis, myocardial infarction, coronary heart disease and othercardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsiaand gastric ulcers.

In one embodiment, the polypeptide can be used for the preparation of amedicament for delaying or preventing disease progression in type 2diabetes.

In one embodiment the polypeptide can be used for the preparation of amedicament for decreasing food intake, decreasing β-cell apoptosis,increasing β-cell function and β-cell mass, and/or for restoring glucosesensitivity to β-cells.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 3 nmol/kg ofsaid derivative. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 30% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg of said derivative. In one embodiment the amylin polypeptideaccording to this invention reduces food intake in rats by more than 40%relative to vehicle within the first 24 hours after single subcutaneousinjection of 3 nmol/kg of said derivative. In one embodiment the amylinpolypeptide according to this invention reduces food intake in rats bymore than 50% relative to vehicle within the first 24 hours after singlesubcutaneous injection of 3 nmol/kg of said derivative. In oneembodiment the amylin polypeptide according to this invention reducesfood intake in rats by more than 60% relative to vehicle within thefirst 24 hours after single subcutaneous injection of 3 nmol/kg of saidderivative. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg of said derivative. In one embodiment the amylin polypeptideaccording to this invention reduces food intake in rats by more than 80%relative to vehicle within the first 24 hours after single subcutaneousinjection of 3 nmol/kg of said derivative

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 3 nmol/kg ofsaid derivative.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 30% relative to vehicle withinthe first 24 hours after single subcutaneous injection of 3 nmol/kg ofsaid derivative. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg of said derivative In one embodiment the amylin polypeptideaccording to this invention reduces food intake in rats by more than 50%relative to vehicle within the first 24 hours after single subcutaneousinjection of 3 nmol/kg of said derivative. In one embodiment the amylinpolypeptide according to this invention reduces food intake in rats bymore than 60% relative to vehicle within the first 24 hours after singlesubcutaneous injection of 3 nmol/kg of said derivative. In oneembodiment the amylin polypeptide according to this invention reducesfood intake in rats by more than 70% relative to vehicle within thefirst 24 hours after single subcutaneous injection of 3 nmol/kg of saidderivative. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg of said derivative

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 25% relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg ofsaid derivative. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 30% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg of said derivative. In one embodiment the amylin polypeptideaccording to this invention reduces food intake in rats by more than 40%relative to vehicle within the first 24 hours after single subcutaneousinjection of 30 nmol/kg of said derivative In one embodiment the amylinpolypeptide according to this invention reduces food intake in rats bymore than 50% relative to vehicle within the first 24 hours after singlesubcutaneous injection of 30 nmol/kg of said derivative. In oneembodiment the amylin polypeptide according to this invention reducesfood intake in rats by more than 60% relative to vehicle within thefirst 24 hours after single subcutaneous injection of 30 nmol/kg of saidderivative. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg of said derivative. In one embodiment the amylin polypeptideaccording to this invention reduces food intake in rats by more than 80%relative to vehicle within the first 24 hours after single subcutaneousinjection of 30 nmol/kg of said derivative. In one embodiment the amylinpolypeptide according to this invention reduces food intake in rats bymore than 90% relative to vehicle within the first 24 hours after singlesubcutaneous injection of 30 nmol/kg of said derivative. In oneembodiment the amylin polypeptide according to this invention reducesfood intake in rats by 100% relative to vehicle within the first 24hours after single subcutaneous injection of 30 nmol/kg of saidderivative Wherein a reduction of food intake by 100% relative tovehicle means that the rat does not eat.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 25% relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 3 nmol/kg ofsaid derivative. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 30% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg of said derivative. In one embodiment the amylin polypeptideaccording to this invention reduces food intake in rats by more than 40%relative to vehicle within the 24 to 48 hours after single subcutaneousinjection of 3 nmol/kg of said derivative In one embodiment the amylinpolypeptide according to this invention reduces food intake in rats bymore than 50% relative to vehicle within the 24 to 48 hours after singlesubcutaneous injection of 3 nmol/kg of said derivative. In oneembodiment the amylin polypeptide according to this invention reducesfood intake in rats by more than 60% relative to vehicle within the 24to 48 hours after single subcutaneous injection of 3 nmol/kg of saidderivative. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg of said derivative. In one embodiment the amylin polypeptideaccording to this invention reduces food intake in rats by more than 80%relative to vehicle within the 24 to 48 hours after single subcutaneousinjection of 3 nmol/kg of said derivative

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 25% relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg ofsaid derivative. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 30% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg of said derivative. In one embodiment the amylin polypeptideaccording to this invention reduces food intake in rats by more than 40%relative to vehicle within the 24 to 48 hours after single subcutaneousinjection of 30 nmol/kg of said derivative In one embodiment the amylinpolypeptide according to this invention reduces food intake in rats bymore than 50% relative to vehicle within the 24 to 48 hours after singlesubcutaneous injection of 30 nmol/kg of said derivative. In oneembodiment the amylin polypeptide according to this invention reducesfood intake in rats by more than 60% relative to vehicle within the 24to 48 hours after single subcutaneous injection of 30 nmol/kg of saidderivative. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg of said derivative. In one embodiment the amylin polypeptideaccording to this invention reduces food intake in rats by more than 80%relative to vehicle within the 24 to 48 hours after single subcutaneousinjection of 30 nmol/kg of said derivative. In one embodiment the amylinpolypeptide according to this invention reduces food intake in rats bymore than 90% relative to vehicle within the 24 to 48 hours after singlesubcutaneous injection of 30 nmol/kg of said derivative. In oneembodiment the amylin polypeptide according to this invention reducesfood intake in rats by 100% relative to vehicle within the 24 to 48hours after single subcutaneous injection of 30 nmol/kg of saidderivative Wherein a reduction of food intake by 100% relative tovehicle means that the rat does not eat.

In one embodiment the amylin polypeptide according to this inventionreduces plasma calcium levels in rats by less than 30% relative tovehicle at any time after single subcutaneous injection of up to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection ofup to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection upto 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection ofup to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces plasma calcium levels in rats by less than 10% relative tovehicle at any time after single subcutaneous injection of up to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces plasma calcium levels in rats by less than 5% relativeto vehicle at any time after single subcutaneous injection of up to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces plasma calcium levels in rats by less than 1% relativeto vehicle at any time after single subcutaneous injection of up to 30nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces plasma calcium levels in rats by less than 30% relative tovehicle at any time after single subcutaneous injection of up to 1-30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection ofup to 1-30 nmol/kg. In one embodiment the amylin polypeptide accordingto this invention reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection upto 1-30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection ofup to 1-30 nmol/kg. In one embodiment the amylin polypeptide accordingto this invention reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection ofup to 1-30 nmol/kg. In one embodiment the amylin polypeptide accordingto this invention reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection ofup to 1-30 nmol/kg. In one embodiment the amylin polypeptide accordingto this invention reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection ofup to 1-30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces plasma calcium levels in rats by less than 30% relative tovehicle at any time after single subcutaneous injection of up to 20-30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection ofup to 20-30 nmol/kg. In one embodiment the amylin polypeptide accordingto this invention reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection upto 20-30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection ofup to 20-30 nmol/kg. In one embodiment the amylin polypeptide accordingto this invention reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection ofup to 20-30 nmol/kg. In one embodiment the amylin polypeptide accordingto this invention reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection ofup to 20-30 nmol/kg. In one embodiment the amylin polypeptide accordingto this invention reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection ofup to 20-30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces plasma calcium levels in rats by less than 30% relative tovehicle at any time after single subcutaneous injection of up to 3nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection ofup to 3 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection upto 3 nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection ofup to 3 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection ofup to 3 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection ofup to 3 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection ofup to 3 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces plasma calcium levels in rats by less than 30% relative tovehicle at any time after single subcutaneous injection of up to 10nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection ofup to 10 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection upto 10 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection ofup to 10 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection ofup to 10 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection ofup to 10 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection ofup to 10 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces plasma calcium levels in rats by less than 30% relative tovehicle at any time after single subcutaneous injection of up to 15nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection ofup to 15 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection upto 15 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection ofup to 15 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection ofup to 15 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection ofup to 15 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection ofup to 15 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces plasma calcium levels in rats by less than 30% relative tovehicle at any time after single subcutaneous injection of up to 20nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection ofup to 20 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection upto 20 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection ofup to 20 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection ofup to 20 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection ofup to 20 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection ofup to 20 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 30% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 30%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 30%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 30%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 30%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 30%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 30%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 30% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 30%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 30%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 30%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 30%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 30%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 30%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 90% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 30%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 30%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 25% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 25% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 90% relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 25% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 25% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 25% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 90% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 25% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 30% relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 25% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 90% relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 25% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 25%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 20% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 30% relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 20% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 20% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 90% relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 20% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 20% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one 25% or more relative to vehicle within the 24 to 48 hours aftersingle subcutaneous injection of 3 nmol/kg and reduces plasma calciumlevels in rats by less than 20% relative to vehicle at any time aftersingle subcutaneous injection of 3 to 30 nmol/kg. In one embodiment theamylin polypeptide according to this invention reduces food intake inrats by more than 30% relative to vehicle within the 24 to 48 hoursafter single subcutaneous injection of 3 nmol/kg and reduces plasmacalcium levels in rats by less than 20% relative to vehicle at any timeafter single subcutaneous injection of 3 to 30 nmol/kg. In oneembodiment the amylin polypeptide according to this invention reducesfood intake in rats by more than 40% relative to vehicle within the 24to 48 hours after single subcutaneous injection of 3 nmol/kg and reducesplasma calcium levels in rats by less than 20% relative to vehicle atany time after single subcutaneous injection of 3 to 30 nmol/kg. In oneembodiment the amylin polypeptide according to this invention reducesfood intake in rats by more than 50% relative to vehicle within the 24to 48 hours after single subcutaneous injection of 3 nmol/kg and reducesplasma calcium levels in rats by less than 20% relative to vehicle atany time after single subcutaneous injection of 3 to 30 nmol/kg. In oneembodiment the amylin polypeptide according to this invention reducesfood intake in rats by more than 60% relative to vehicle within the 24to 48 hours after single subcutaneous injection of 3 nmol/kg and reducesplasma calcium levels in rats by less than 20% relative to vehicle atany time after single subcutaneous injection of 3 to 30 nmol/kg. In oneembodiment the amylin polypeptide according to this invention reducesfood intake in rats by more than 70% relative to vehicle within the 24to 48 hours after single subcutaneous injection of 3 nmol/kg and reducesplasma calcium levels in rats by less than 20% relative to vehicle atany time after single subcutaneous injection of 3 to 30 nmol/kg. In oneembodiment the amylin polypeptide according to this invention reducesfood intake in rats by more than 80% relative to vehicle within the 24to 48 hours after single subcutaneous injection of 3 nmol/kg and reducesplasma calcium levels in rats by less than 20% relative to vehicle atany time after single subcutaneous injection of 3 to 30 nmol/kg. In oneembodiment the amylin polypeptide according to this invention reducesfood intake in rats by more than 90% relative to vehicle within the 24to 48 hours after single subcutaneous injection of 3 nmol/kg and reducesplasma calcium levels in rats by less than 20% relative to vehicle atany time after single subcutaneous injection of 3 to 30 nmol/kg. In oneembodiment the amylin polypeptide according to this invention reducesfood intake in rats by more than 100% relative to vehicle within the 24to 48 hours after single subcutaneous injection of 3 nmol/kg and reducesplasma calcium levels in rats by less than 20% relative to vehicle atany time after single subcutaneous injection of 3 to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 20% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 30% relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 20% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 20% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 90% relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 20% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 20%relative

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 15% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 30% relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 15% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 15% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 90% relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 15% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 15% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 30% relative to vehicle withinthe first 24 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 15% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 15% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 30% relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 15% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 90% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 15% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 30% relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 15% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 15% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 90% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 15%relative

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 10% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 10% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 90% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 10% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 30% relative to vehicle withinthe first 24 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 10% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 30% relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 10% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 90% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 10% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 10% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 90% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 10%relative

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or morerelative to vehicle within thefirst 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 5% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 5% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 30% relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 5% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 90% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 5% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 30% relative to vehicle withinthe first 24 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 5% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 5% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 30% relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 5% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 90% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 5% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 5% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 90% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 5%relative

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 25% relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 1% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 325% relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 1% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 90% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 1% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by more than 30% relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 3 nmol/kg andreduces plasma calcium levels in rats by less than 1% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 90% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of3 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe first 24 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 1% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the first 24 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg.

In one embodiment the amylin polypeptide according to this inventionreduces food intake in rats by 25% or more relative to vehicle withinthe 24 to 48 hours after single subcutaneous injection of 30 nmol/kg andreduces plasma calcium levels in rats by less than 1% relative tovehicle at any time after single subcutaneous injection of 3 to 30nmol/kg. In one embodiment the amylin polypeptide according to thisinvention reduces food intake in rats by more than 30% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 40% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 50% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 60% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 70% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 80% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 90% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative to vehicle at any time after single subcutaneous injection of 3to 30 nmol/kg. In one embodiment the amylin polypeptide according tothis invention reduces food intake in rats by more than 100% relative tovehicle within the 24 to 48 hours after single subcutaneous injection of30 nmol/kg and reduces plasma calcium levels in rats by less than 1%relative

The above embodiments are represented experimentally in table 15.

The treatment with a polypeptide according to the present invention mayalso be combined with a second or more pharmacologically activesubstances, e.g. selected from antidiabetic agents, antiobesity agents,appetite regulating agents, antihypertensive agents, agents for thetreatment and/or prevention of complications resulting from orassociated with diabetes and agents for the treatment and/or preventionof complications and disorders resulting from or associated withobesity. Examples of these pharmacologically active substances are:Insulin, insulin derivative, insulin analogues, GLP-1, GLP-1derivatives, GLP-1 analogues, oxyntomodulin derivatives, sulphonylureas,biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists,DPP-IV (dipeptidyl peptidase-IV) inhibitors, inhibitors of hepaticenzymes involved in stimulation of gluconeogenesis and/orglycogenolysis, glucose uptake modulators, compounds modifying the lipidmetabolism such as antihyperlipidemic agents as HMG CoA inhibitors(statins), compounds lowering food intake, RXR agonists and agentsacting on the ATP-dependent potassium channel of the β-cells;Cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin,pravastatin, simvastatin, probucol, dextrothyroxine, neteglinide,repaglinide; β-blockers such as alprenolol, atenolol, timolol, pindolol,propranolol and metoprolol, ACE (angiotensin converting enzyme)inhibitors such as benazepril, captopril, enalapril, fosinopril,lisinopril, alatriopril, quinapril and ramipril, calcium channelblockers such as nifedipine, felodipine, nicardipine, isradipine,nimodipine, diltiazem and verapamil, and α-blockers such as doxazosin,urapidil, prazosin and terazosin; CART (cocaine amphetamine regulatedtranscript) agonists, NPY (neuropeptide Y) antagonists, MC4(melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosisfactor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP(corticotropin releasing factor binding protein) antagonists, urocortinagonists, β3 agonists, MSH (melanocyte-stimulating hormone) agonists,MCH (melanocyte-concentrating hormone) antagonists, CCK(cholecystokinin) agonists, serotonin re-uptake inhibitors, serotoninand noradrenaline re-uptake inhibitors, mixed serotonin andnoradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists,galanin antagonists, growth hormone, growth hormone releasing compounds,TRH (thyrotropin releasing hormone) agonists, UCP 2 or 3 (uncouplingprotein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin,doprexin), lipase/amylase inhibitors, RXR (retinoid X receptor)modulators, TR β agonists; histamine H3 antagonists, gastrin and gastrinanalogs.

It should be understood that any suitable combination of thepolypeptides according to the invention with one or more of theabove-mentioned compounds and optionally one or more furtherpharmacologically active substances are considered to be within thescope of the present invention.

The invention will be further summarised but not limited in theparagraphs below:

1. A polypeptide selected from:

-   -   (i) a polypeptide comprising an amino acid sequence which is an        analogue of SEQ ID No: 1 wherein:        -   (a) said analogue comprises a proline residue at position            21;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1;        -   optionally wherein (b) the polypeptide has an IC₅₀ in a            human amylin receptor binding assay of about 1200 pM or            less;        -   optionally wherein the polypeptide has at least one            substituent attached to at least one of its amino acid            residues;    -   (ii) a polypeptide comprising an amino acid sequence which is an        analogue of SEQ ID No: 1 wherein:        -   (a) said analogue comprises a proline residue at position            21; and        -   (b) said polypeptide has an IC₅₀ in a human amylin receptor            binding assay of about 1200 pM or less;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1;    -   (iii) a polypeptide comprising an amino acid sequence which is        an analogue of SEQ ID No: 1 wherein:        -   (a) said analogue comprises a proline residue at position            21;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1; and        -   wherein the polypeptide has at least one substituent            attached to at least one of its amino acid residues; and    -   (iv) a polypeptide comprising an amino acid sequence which is an        analogue of SEQ ID No: 1 wherein:        -   (a) said analogue comprises a proline residue at position            21; and        -   (b) said polypeptide has an IC₅₀ in a human amylin receptor            binding assay of about 1200 pM or less;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1; and        -   wherein the polypeptide has at least one substituent            attached to at least one of its amino acid residues.

1A. A polypeptide selected from:

-   -   (i) a polypeptide according to SEQ ID No: 1 wherein:        -   (a) said polypeptide comprises a proline residue at position            21;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1;        -   optionally wherein (b) the polypeptide has an IC₅₀ in a            human amylin receptor binding assay of about 1200 pM or            less;        -   optionally wherein the polypeptide has at least one            substituent attached to at least one of its amino acid            residues;    -   (ii) a polypeptide according to SEQ ID No: 1 wherein:        -   (a) said polypeptide comprises a proline residue at position            21; and        -   (b) said polypeptide has an IC₅₀ in a human amylin receptor            binding assay of about 1200 pM or less;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1;    -   (iii) a polypeptide according to SEQ ID No: 1 wherein:        -   (a) said polypeptide comprises a proline residue at position            21;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1; and        -   wherein the polypeptide has at least one substituent            attached to at least one of its amino acid residues; and    -   (iv) a polypeptide according to SEQ ID No: 1 wherein:        -   (a) said polypeptide comprises a proline residue at position            21; and        -   (b) said polypeptide has an IC₅₀ in a human amylin receptor            binding assay of about 1200 pM or less;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1; and        wherein the polypeptide has at least one substituent attached to        at least one of its amino acid residues.

1B. A polypeptide selected from:

-   -   (i) a polypeptide according to SEQ ID No: 1 having about a        10-fold or greater selectivity for binding to the human amylin        receptor over binding to the human calcitonin receptor and        wherein:        -   (a) said polypeptide comprises a proline residue at position            21;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1;        -   optionally wherein (b) the polypeptide has an IC₅₀ in a            human amylin receptor binding assay of about 1200 pM or            less;        -   optionally wherein the polypeptide has at least one            substituent attached to at least one of its amino acid            residues;    -   (ii) a polypeptide according to SEQ ID No: 1 having about a        10-fold or greater selectivity for binding to the human amylin        receptor over binding to the human calcitonin receptor and        wherein:        -   (a) said polypeptide comprises a proline residue at position            21; and        -   (b) said polypeptide has an IC₅₀ in a human amylin receptor            binding assay of about 1200 pM or less;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1;    -   (iii) a polypeptide according to SEQ ID No: 1 having about a        10-fold or greater selectivity for binding to the human amylin        receptor over binding to the human calcitonin receptor and        wherein:        -   (a) said polypeptide comprises a proline residue at position            21;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1; and        -   wherein the polypeptide has at least one substituent            attached to at least one of its amino acid residues; and    -   (iv) a polypeptide according to SEQ ID No: 1 having about a        10-fold or greater selectivity for binding to the human amylin        receptor over binding to the human calcitonin receptor and        wherein:        -   (a) said polypeptide comprises a proline residue at position            21; and        -   (b) said polypeptide has an IC₅₀ in a human amylin receptor            binding assay of about 1200 pM or less;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1; and        wherein the polypeptide has at least one substituent attached to        at least one of its amino acid residues.

1C. A polypeptide selected from:

-   -   (i) an analogue of SEQ ID No: 1 wherein:        -   (a) said analogue comprises a proline residue at position            21;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1;        -   optionally wherein (b) the polypeptide has an IC₅₀ in a            human amylin receptor binding assay of about 1200 pM or            less;        -   optionally wherein the polypeptide has at least one            substituent attached to at least one of its amino acid            residues;    -   (ii) a polypeptide according to SEQ ID No: 1 wherein:        -   (a) said analogue comprises a proline residue at position            21; and        -   (b) said polypeptide has an IC₅₀ in a human amylin receptor            binding assay of about 1200 pM or less;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1;    -   (iii) a polypeptide according to SEQ ID No: 1 wherein:        -   (a) said analogue comprises a proline residue at position            21;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1; and        -   wherein the polypeptide has at least one substituent            attached to at least one of its amino acid residues; and    -   (iv) a polypeptide according to SEQ ID No: 1 wherein:        -   (a) said analoguecomprises a proline residue at position 21;            and        -   (b) said polypeptide has an IC₅₀ in a human amylin receptor            binding assay of about 1200 pM or less;    -   wherein the amino acid sequence numbering of the analogue        corresponds to the amino acid numbering sequence of SEQ ID No:        1; and        wherein the polypeptide has at least one substituent attached to        at least one of its amino acid residues.

2. The polypeptide according to paragraph 1 which further has about a10-fold or greater selectivity for binding to the human amylin receptorover binding to the human calcitonin receptor.

2A. The polypeptide according to paragraph 1 which further has about a15-fold or greater selectivity for binding to the human amylin receptorover binding to the human calcitonin receptor.

2B. The polypeptide according to paragraph 1 which further has about a20-fold or greater selectivity for binding to the human amylin receptorover binding to the human calcitonin receptor.

2C. The polypeptide according to paragraph 1 which further has about a10 to 20-fold or greater selectivity for binding to the human amylinreceptor over binding to the human calcitonin receptor.

3. The polypeptide according to any one of paragraphs 1 and 2 whereinthe analogue comprises a proline or leucine residue at position 27,preferably proline.

4. The polypeptide according to any preceding paragraph wherein theanalogue comprises a valine or arginine residue at position 17,preferably arginine.

5. The polypeptide according to any preceding paragraph wherein theanalogue comprises an amino acid residue at position 1 selected fromlysine, glycine and arginine; preferably lysine.

6. The polypeptide according to any preceding paragraph wherein theanalogue comprises an amino acid residue at position 14 selected fromaspartic acid, glutamic acid, histidine, asparagine, glycine, alanine,serine, lysine, threonine and cysteine; preferably selected fromaspartic acid and glutamic acid; more preferably aspartic acid.

7. The polypeptide according to any preceding paragraph wherein theanalogue comprises an amino acid residue at position 25 selected fromproline and alanine; preferably alanine.

8. The polypeptide according to any preceding paragraph wherein theanalogue comprises an amino acid residue at position 26 selected fromproline and isoleucine, preferably isoleucine.

9. The polypeptide according to any preceding paragraph wherein theanalogue comprises an amino acid residue at position 28 selected fromproline and serine, preferably serine.

10. The polypeptide according to any preceding paragraph wherein theanalogue comprises an amino acid residue at position 29 selected fromproline or serine, preferably serine.

11. The polypeptide according to any preceding paragraph wherein theanalogue comprises an amino acid residue at position 31 selected fromproline and asparagine, preferably asparagine.

12. The polypeptide according to any preceding paragraph wherein theanalogue comprises an amino acid residue at position 34 selected fromproline, histidine, lysine, arginine and serine, preferably proline andserine, more preferably serine.

13. The polypeptide according to any preceding paragraph wherein theanalogue comprises an amino acid residue at position 35 selected fromaspartic acid, arginine, glutamic acid, lysine, histidine andasparagine, preferably asparagine and arginine, more preferablyarginine.

14. The polypeptide according to any preceding paragraph wherein theanalogue comprises an amino acid residue at position 37 selected fromproline and tyrosine, preferably tyrosine.

15. The polypeptide according to any preceding paragraph wherein theanalogue comprises an amino acid residue at position 14 which isaspartic acid, an amino acid residue at position 17 which is arginine,an amino acid residue at position 21 which is proline, an amino acidresidue at position 27 which is proline and an amino acid residue atposition 35 which is arginine.

15A. The polypeptide according to any of the paragraphs 1-14 (includingthe alternatives A, B, C) wherein the analogue comprises an amino acidresidue at position 21 which is proline, an amino acid residue atposition 27 which is proline and an amino acid residue at position 35which is arginine.

15B. The polypeptide according to any of the paragraphs 1-14 (includingthe alternatives A, B, C) wherein the analogue comprises an amino acidresidue at position 14 which is aspartic acid, an amino acid residue atposition 21 which is proline, an amino acid residue at position 27 whichis proline and an amino acid residue at position 35 which is arginine.

16. The polypeptide according any preceding paragraph wherein theanalogue comprises the same amino acid residue at positions 2 to 13, 15to 20, 22, 23, 24, 30, 32, 33 and 36 as the residues at positions 2 to13, 15 to 20, 22, 23, 24, 30, 32, 33 and 36 of SEQ ID No: 1respectively.

17. A polypeptide according to any one of paragraphs 1 and 2 comprisingan analogue of SEQ ID No: 1 of formula (I):

(I) Xaa₁-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Xaa₁₄-Phe-Leu-Xaa₁₇-His-Ser-Ser-Xaa₂₁-Asn-Phe-Gly-Xaa₂₅-Xaa₂₆-Xaa₂₇-Xaa₂₈-Xaa₂₉-Thr-Xaa₃₁-Val-Gly-Xaa₃₄-Xaa₃₅-Thr-Tyr; wherein

-   -   Xaa₁ is independently selected from Gly, Arg and Lys;    -   Xaa₁₄ is independently selected from Asp, Glu, His, Arg, Gly,        Ala, Ser, Lys, Thr and Cys;    -   Xaa₁₇ is independently selected from Arg and Val;    -   Xaa₂₁ is Pro;    -   Xaa₂₅ is independently selected from Pro and Ala;    -   Xaa₂₆ is independently selected from Pro and Ile;    -   Xaa₂₇ is independently selected from Pro and Leu;    -   Xaa₂₈ is independently selected from Pro and Ser;    -   Xaa₂₉ is independently selected from Pro and Ser;    -   Xaa₃₁ is independently selected from Pro and Asn;    -   Xaa₃₄ is independently selected from Pro, His, Lys, Arg and Ser    -   Xaa₃₅ is independently selected from Asp, Arg, Glu, Lys, His and        Asn;    -   Xaa₃₇ is independently selected from Pro and Tyr;    -   and where the C-terminal may optionally be derivatized.

17A. A polypeptide according to any one of paragraphs 1 and 2 comprisingan analogue of SEQ ID No: 1 of formula (I):

(I) Xaa₁-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Xaa₁₄-Phe-Leu-Xaa₁₇-His-Ser-Ser-Xaa₂₁-Asn-Phe-Gly-Xaa₂₅-Xaa₂₆-Xaa₂₇-Xaa₂₈-Xaa₂₉-Thr-Xaa₃₁-Val-Gly-Xaa₃₄-Xaa₃₅-Thr-Xaa₃₇;wherein

-   -   Xaa₁ is independently selected from Gly, Arg and Lys;    -   Xaa₁₄ is independently selected from Asp, Glu, His, Arg, Gly,        Ala, Ser, Lys, Thr and Cys;    -   Xaa₁₇ is independently selected from Arg and Val;

Xaa₂₁ is Pro;

-   -   Xaa₂₅ is independently selected from Pro and Ala;    -   Xaa₂₆ is independently selected from Pro and Ile;    -   Xaa₂₇ is independently selected from Pro and Leu;    -   Xaa₂₈ is independently selected from Pro and Ser;    -   Xaa₂₉ is independently selected from Pro and Ser;    -   Xaa₃₁ is independently selected from Pro and Asn;    -   Xaa₃₄ is independently selected from Pro, His, Lys, Arg and Ser    -   Xaa₃₅ is independently selected from Asp, Arg, Glu, Lys, His and        Asn;    -   Xaa₃₇ is independently selected from Pro and Tyr;    -   and where the C-terminal may optionally be derivatized.

18. A polypeptide according to any one of paragraphs 1 and 2 consistingof an analogue of SEQ ID No: 1 of formula (I) as defined in paragraph17.

19. The polypeptide according to any one of paragraphs 17 and 18 whereinXaa₂₇ is Pro.

20. The polypeptide according to any one of paragraphs 17 to 19 whereinXaa₁₇ is Arg.

21. The polypeptide according to any one of paragraphs 17 to 20 whereinXaa₃₇ is Tyr.

22. The polypeptide according to any one of paragraphs 17 to 21 whereinXaa₁₄ is selected from Asp and Glu, preferably Asp.

23. The polypeptide according to any one of paragraphs 17 to 22 whereinXaa₃₅ is selected from Asn and Arg, preferably Arg.

24. The polypeptide according to any one of paragraphs 17 to 23 whereinXaa₃₄ is selected from Pro and Ser, preferably Ser.

25. The polypeptide according to any one of paragraphs 17 to 24 whereinXaa₁ is Lys.

26. The polypeptide according to any one of paragraphs 17 to 25 whereinXaa₁ is Lys, Xaa₁₄ is Asp, Xaa₁₇ is Arg, Xaa₂₁ is Pro, Xaa₂₅ is Ala,Xaa₂₆ is Ile, Xaa₂₇ is Pro, Xaa₂₈ is Ser, Xaa₂₉ is Ser, Xaa₃, is Asn,Xaa₃₄ is Ser, Xaa₃₅ is Asn, Xaa₂₇ is Tyr.

26A. The polypeptide according to any one of paragraphs 17 to 25 whereinXaa₁ is Lys, Xaa₁₄ is Asp, Xaa₁₇ is Arg, Xaa₂₁ is Pro, Xaa₂₅ is Ala,Xaa₂₆ is Ile, Xaa₂₇ is Pro, Xaa₂₈ is Ser, Xaa₂₉ is Ser, Xaa₃₁ is Asn,Xaa₃₄ is Ser, Xaa₃₅ is Asn, Xaa₃₇ is Tyr.

27. The polypeptide according to any one of the preceding paragraphscomprising a C-terminal amide.

28. The polypeptide according to any one of the preceding paragraphswherein at least one substituent is attached to one of the amino acidresidues.

29. The polypeptide according to paragraph 28 wherein the substituent isselected from a hydrocarbyl group, a hydroxyl group and a halogen atom.

30. The polypeptide according to paragraphs 29 wherein the substituentgroup is of formula (II):

L_(n)-Y  (II)

-   -   wherein    -   L is a linker;    -   n=0 or 1    -   Y is an albumin binding moiety.

31. The polypeptide according to paragraph 30 wherein the albuminbinding moiety is an acyl group selected from:

-   -   (a) CH₃(CH₂)_(r)CO—, wherein r is an integer from 12 to 20;    -   (b) HOOC(CH₂)_(s)CO—, wherein s is an integer from 12 to 22 or s        is an integer from 12 to 18, or s is 16 to 18 or preferably s is        18.

32. The polypeptide according to any one of paragraphs 30 and 31 whereinthe linker is selected from the group consisting of γGlu, γGlu-γGlu,γGlu-γGlu-γGlu, γGlu-γGlu-γGlu-γGlu, Glu, Glu-Glu, Glu-γGlu, Glu-Arg,Glu-Glu-Arg, His, His-His, His-γGlu, His-His-γGlu, Gly, Gly-γGlu, Ser,Ser-γGlu, D-Arg-D-Arg, Arg, Arg-Arg, Arg-Arg-γGlu, Ser-Ser,-Gly-Ser-Ser, Ser-Ser, -Gly-Ser-Ser-γGlu, Ser-Ser-Gly-Ser-Ser-Gly andSer-Ser-Gly-Ser-Ser-Gly-γGlu, γGlu-OEG, γGlu-OEG-OEG and OEG, preferablythe linker is selected from γGlu, γGlu-γGlu, γGlu-OEG, γGlu-OEG-OEG andOEG, more preferably the linker is γGlu-γGlu.

33. The polypeptide according to any one of paragraphs 29 to 32 whereinthe substituent group is selected from the groups presented in Table 1(presented earlier).

34. The polypeptide according to any one of paragraphs 28 to 33 whereina substituent is attached to the α-amino group of the N-terminal aminoacid residue or to a Lys residue.

35. The polypeptide according to any one of paragraphs 28 to 34 whereina substituent is attached to the N-terminal amino acid residue or to alysine residue via the &amino group, preferably the substituent isattached to a lysine residue via the &amino group.

36. The polypeptide according any one of paragraphs 28 to 35 wherein thesubstitutent is attached to a lysine residue at position 1 only.

37. The polypeptide according to paragraph 36 wherein the substituent isattached to the lysine residue either via the α-amino group or via the&amino group, preferably the substituent is attached to a lysine residuevia the &amino group.

38. The polypeptide according to any preceding paragraphs selected fromthe group consisting of any of the polypeptides presented in Table 2(presented earlier) or from the group consisting of any of thepolypeptides presented in Table 3 (presented earlier) or from the groupconsisting of any of the polypeptides presented in Table 4 (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 5 (presented later) or from the group consisting of any of thepolypeptides presented in Table 5a (presented later) or from the groupconsisting of any of the polypeptides presented in Table 6 (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 6a (presented later) or from the group consisting of any of thepolypeptides presented in Table 7 (presented later) or from the groupconsisting of any of the polypeptides presented in Table 7a (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 7b (presented later) or from the group consisting of any of thepolypeptides presented in Table 8 (presented later) or from the groupconsisting of any of the polypeptides presented in Table 9 (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 10 (presented later) or from the group consisting of any of thepolypeptides presented in Table 11 (presented later) from the groupconsisting of any of the polypeptides presented in Table 12 (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 13 (presented later) or from the group consisting of any of thepolypeptides presented in Table 14 (presented later).

38A. The polypeptide according to any of the preceding paragraphsselected from the group consisting of the polypeptides in Table 2(presented earlier) or from the group consisting of any of thepolypeptides presented in Table 3 (presented earlier) or from the groupconsisting of any of the polypeptides presented in Table 4 (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 4a (presented later) or from the group consisting of any of thepolypeptides presented in Table 4b (presented later) or from the groupconsisting of any of the polypeptides presented in Table 4c (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 5 (presented later) or from the group consisting of any of thepolypeptides presented in Table 5a (presented later) or from the groupconsisting of any of the polypeptides presented in Table 5b (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 5c (presented later) or from the group consisting of any of thepolypeptides presented in Table 6 (presented later) or from the groupconsisting of any of the polypeptides presented in Table 6a (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 6b (presented later) or from the group consisting of any of thepolypeptides presented in Table 6c (presented later) or from the groupconsisting of any of the polypeptides presented in Table 6d (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 6e (presented later) or from the group consisting of any of thepolypeptides presented in Table 6f (presented later) or from the groupconsisting of any of the polypeptides presented in Table 6g (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 6h (presented later) or from the group consisting of any of thepolypeptides presented in Table 6i (presented later) or from the groupconsisting of any of the polypeptides presented in Table 6j (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 6k (presented later) or from the group consisting of any of thepolypeptides presented in Table 6l (presented later) or from the groupconsisting of any of the polypeptides presented in Table 6m (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 6n (presented later) or from the group consisting of any of thepolypeptides presented in Table 6o (presented later) or from the groupconsisting of any of the polypeptides presented in Table 7 (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 7a (presented later) or from the group consisting of any of thepolypeptides presented in Table 7b (presented later) or from the groupconsisting of any of the polypeptides presented in Table 7c (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 8 (presented later) or from the group consisting of any of thepolypeptides presented in Table 8a (presented later) or from the groupconsisting of any of the polypeptides presented in Table 9 (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 9a (presented later) or from the group consisting of any of thepolypeptides presented in Table 10 (presented later) or from the groupconsisting of any of the polypeptides presented in Table 11 (presentedlater) from the group consisting of any of the polypeptides presented inTable 12 (presented later) or from the group consisting of any of thepolypeptides presented in Table 13 (presented later) or from the groupconsisting of any of the polypeptides presented in Table 14 (presentedlater).

39. The polypeptide according to any preceding paragraphs selected fromthe group consisting of any of the polypeptides presented in Table 5a(presented later) or from the group consisting of any of thepolypeptides presented in Table 6a (presented later) or from the groupconsisting of any of the polypeptides presented in Table 7a (presentedlater) or from the group consisting of any of the polypeptides presentedin Table 7b (presented later).

40. The polypeptide according to any one of the preceding paragraphswherein said polypeptide is:

N-ε-1-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxynonadecanoylamino)butyrylamino]butyryl}-[Asp14,Arg17,Pro21,Pro27,Arg35]-humanamylin. The amino acid sequence of said polypeptide is designated as SEQID NO: 4.

40A. The polypeptide according to any one of the preceding paragraphswherein said polypeptide is:

N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Asp14,Arg17,Pro21,Pro27,Arg35]-h-amylin.The amino acid sequence of said polypeptide is designated as SEQ ID NO:4.

41. A pharmaceutical composition comprising a polypeptide according toany of the preceding paragraphs and a pharmaceutically acceptableexcipient.

42. The pharmaceutical composition according to paragraph 41, which issuited for parenteral administration.

43. A process for preparing a pharmaceutical composition according toparagraph 41 or paragraph 42 comprising mixing a polypeptide accordingto any preceding paragraph with at least one pharmaceutically acceptableexcipient.

44. A polypeptide according to any of the preceding paragraphs for useas a medicament.

45. A polypeptide according to any one of the preceding paragraphs foruse in the treatment or prevention of hyperglycemia, type 2 diabetes,impaired glucose tolerance, type 1 diabetes, obesity, hypertension,syndrome X, dyslipidemia, cognitive disorders, atherosclerosis,myocardial infarction, coronary heart disease and other cardiovasculardisorders, stroke, inflammatory bowel syndrome, dyspepsia and gastriculcers.

46. A polypeptide according to any one of the preceding paragraphs foruse in delaying or preventing disease progression in type 2 diabetes.

47. A polypeptide according to any one of the preceding paragraphs foruse in preventing or treating obesity.

48. A polypeptide according to any one of the preceding paragraphs foruse in decreasing food intake, decreasing β-cell apoptosis, increasingβ-cell function and β-cell mass, and/or for restoring glucosesensitivity to β-cells.

49. A method of treating or preventing hyperglycemia, type 2 diabetes,impaired glucose tolerance, type 1 diabetes, obesity, hypertension,syndrome X, dyslipidemia, cognitive disorders, atherosclerosis,myocardial infarction, coronary heart disease and other cardiovasculardisorders, stroke, inflammatory bowel syndrome, dyspepsia and gastriculcers by administering a polypeptide according to any precedingparagraph to an animal.

50. A method of delaying or preventing disease progression in type 2diabetes by administering a polypeptide according to any precedingparagraph to an animal.

51. A method of decreasing food intake, decreasing β-cell apoptosis,increasing β-cell function and β-cell mass, and/or for restoring glucosesensitivity to β-cells by administering a polypeptide according to anypreceding paragraph to an animal.

52. The invention according to any one of the preceding paragraphswherein said polypeptide has an IC₅₀ in a human amylin receptor bindingassay of about 1200 pM or less.

53. The invention according to any one of the preceding paragraphswherein said polypeptide reduces food intake in rats by 25% or morerelative to vehicle within the first 24 hours after single subcutaneousinjection of 3 nmol/kg and reduces plasma calcium levels in rats by lessthan 30% relative to vehicle at any time after single subcutaneousinjection of 3 to 30 nmol/kg.

54. The invention according to any one of the preceding paragraphswherein said polypeptide reduces food intake in rats by 25% or morerelative to vehicle within the first 24 hours after single subcutaneousinjection of 3 nmol/kg and reduces plasma calcium levels in rats by lessthan 30% relative to vehicle at any time after single subcutaneousinjection of 3 to 30 nmol/kg.

55. The invention according to any one of the preceding paragraphswherein said polypeptide reduces food intake in rats by 30% or morerelative to vehicle within the first 24 hours after single subcutaneousinjection of 3 nmol/kg and reduces plasma calcium levels in rats by lessthan 30% relative to vehicle at any time after single subcutaneousinjection of 3 to 30 nmol/kg.

56. The invention according to any one of the preceding paragraphswherein said polypeptide reduces food intake in rats by 25% or morerelative to vehicle within the first 24 hours after single subcutaneousinjection of 30 nmol/kg and reduces plasma calcium levels in rats byless than 30% relative to vehicle at any time after single subcutaneousinjection of 3 to 30 nmol/kg.

57. The invention according to any one of the preceding paragraphswherein said polypeptide reduces food intake in rats by 30% or morerelative to vehicle within the first 24 hours after single subcutaneousinjection of 30 nmol/kg and reduces plasma calcium levels in rats byless than 30% relative to vehicle at any time after single subcutaneousinjection of 3 to 30 nmol/kg.

The invention will be further summarised but not limited in theparagraphs below:

1. A polypeptide which is an analogue of SEQ ID No: 1 having about a10-fold or greater selectivity for binding to the human amylin receptorover binding to the human calcitonin receptor and wherein:

(a) said analogue of SEQ ID No: 1 comprises a proline residue atposition 21;wherein the amino acid sequence numbering of the analogue corresponds tothe amino acid numbering sequence of SEQ ID No: 1; and(b) wherein the polypeptide has at least one substituent attached to atleast one of its amino acid residues and optionally(c) wherein the polypeptide has an IC₅₀ in a human amylin receptorbinding assay of about 1200 pM or less.

2. The polypeptide according to any one of paragraphs 1 and 2 whereinthe analogue comprises a proline or leucine residue at position 27.

3. The polypeptide according to any one of paragrahps 1 and 2 whereinthe analogue comprises a proline residue at position 27.

4. The polypeptide according any preceding paragraph wherein theanalogue comprises an amino acid residue at position 14 which isaspartic acid, an amino acid residue at position 17 which is arginine,an amino acid residue at position 21 which is proline, an amino acidresidue at position 27 which is proline and an amino acid residue atposition 35 which is arginine.

5. A polypeptide according to any one of paragraphs 1 and 2 comprisingan analogue of SEQ ID No: 1 according to formula (I):

(I) Xaa₁-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Xaa₁₄-Phe-Leu-Xaa₁₇-His-Ser-Ser-Xaa₂₁-Asn-Phe-Gly-Xaa₂₅-Xaa₂₆-Xaa₂₇-Xaa₂₈-Xaa₂₉-Thr-Xaa₃₁-Val-Gly-Xaa₃₄-Xaa₃₅-Thr-Xaa₃₇;whereinXaa₁ is independently selected from Ala, Cys, Glu, Gly, His, Arg, Serand Lys;Xaa₁₄ is independently selected from Asp, Glu, His, Asn, Arg, Gly, Ala,Ser, Lys, Thr and Cys;Xaa₁₇ is independently selected from Arg and Val;

Xaa₂₁ is Pro;

Xaa₂₅ is independently selected from Pro and Ala;Xaa₂₆ is independently selected from Pro and Ile;Xaa₂₇ is independently selected from Pro and Leu;Xaa₂₈ is independently selected from Pro and Ser;Xaa₂₉ is independently selected from Pro and Ser;Xaa₃₁ is independently selected from Pro and Asn;Xaa₃₄ is independently selected from Pro, His, Lys, Arg and SerXaa₃₅ is independently selected from Asp, Arg, Glu, Lys, His and Asn;Xaa₃₇ is independently selected from Pro and Tyr;and where the C-terminal may optionally be derivatized.

6. The polypeptide according to paragraph 5 wherein Xaa₁ is Lys, Xaa₁₄is Asp, Xaa₁₇ is Arg, Xaa₂₁ is Pro, Xaa₂₅ is Ala, Xaa₂₆ is Ile, Xaa₂₇ isPro, Xaa₂₈ is Ser, Xaa₂₉ is Ser, Xaa₃₁ is Asn, Xaa₃₄ is Ser, Xaa₃₅ isAsn, Xaa₃₇ is Tyr. (SEQ ID NO:3)

7. The polypeptide according to paragraph 7 wherein the substituentgroup is selected from any of the substituent groups presented in Table1 (presented earlier).

8. The polypeptide according to any preceding paragraph wherein asubstituent is attached to the α-amino group of the N-terminal aminoacid residue or to a Lys residue or cysteine residue only.

9. The polypeptide according to any of the preceding paragraphs eitherselected from the group consisting of any of the polypeptides presentedin Table 2 (presented earlier) or selected from the group consisting ofany of the polypeptides presented in Table 3 (presented earlier).

10. The polypeptide according to any of the preceding paragraphs whereinthe polypeptide isN-ε-1-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxynonadecanoylamino)butyrylamino]butyryl}-Asp14,Arg17,Pro21,Pro27,Arg35]-humanamylin.

11. A polypeptide according to any of the preceding paragraphs for useas a medicament.

12. A polypeptide according to any of the preceding paragraphs eitherfor use in the treatment or prevention of hyperglycemia, type 2diabetes, impaired glucose tolerance, type diabetes, obesity,hypertension, syndrome X, dyslipidemia, cognitive disorders,atherosclerosis, myocardial infarction, coronary heart disease and othercardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsiaand gastric ulcers and/or for use in decreasing food intake, decreasingn-cell apoptosis, increasing n-cell function and n-cell mass, and/or forrestoring glucose sensitivity to n-cells.

13. The invention according to any one of the preceding paragraphswherein said polypeptide reduces food intake in rats by 25% or morerelative to vehicle within the first 24 hours after single subcutaneousinjection of 3 nmol/kg and reduces plasma calcium levels in rats by lessthan 30% relative to vehicle at any time after single subcutaneousinjection of 3 to 30 nmol/kg.

14. A pharmaceutical composition comprising a polypeptide according toany of the preceding paragraphs and a pharmaceutically acceptableexcipient.

15. A process for preparing a pharmaceutical composition according toparagraph 14 comprising mixing a polypeptide according to any precedingparagraph with at least one pharmaceutically acceptable excipient.

The present invention will now be described only by way of examples.

EXAMPLES Abbreviations

Some of the abbreviations used in the Examples are as follows:

-   -   Acm: acetamidomethyl    -   HATU: (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate)    -   HBTU: 2-(1H-Benzotriazol-1-yl-)-1,1,3,3 tetramethyluronium        hexafluorophosphate    -   Fmoc: 9H-fluoren-9-ylmethoxycarbonyl    -   Boc: tert butyloxycarbonyl    -   Mtt: 4-methyltrityl    -   DCM: dichloromethane    -   TIPS: triisopropylsilane    -   TFA: trifluoroacetic acid    -   NMP: 1-Methyl-pyrrolidin-2-one    -   HOAt: 1-Hydroxy-7-azabenzotriazole    -   DIC: Diisopropylcarbodiimide    -   Trt: triphenylmethyl

Assays

In the following examples reference is made to the following Assays:

-   -   ASSAY (I)— Experimental protocol for efficacy testing on        appetite using an ad libitum fed rat model    -   ASSAY (II)a—Functional assay—Human calcitonin and amylin        receptor assay    -   ASSAY (II)b—Functional assay—Rat calcitonin and rat amylin        receptor assays    -   ASSAY (III)—ThT fibrillation assays for the assessment of        physical stability of protein formulations    -   ASSAY (IV)—Determination of solubility    -   ASSAY (V)—Determination of binding to the human amylin receptor    -   ASSAY (VI)—Determination of the binding to the rat amylin        receptor    -   ASSAY (VII)—Determination of binding to the human calcitonin        receptor    -   ASSAY (VIII)—Determination of binding to the rat calcitonin        receptor    -   ASSAY (IX)— pK—Determination of T½ in mini-pig    -   ASSAY (X)—pK—Determination of T½ in rat    -   ASSAY (XI)—Effect from single subcutaneous administration of        analogue on plasma calcium in rats    -   ASSAY (XII)—Effect from single subcutaneous administration of        analogue on plasma calcium in rats

Assay (I)— Experimental Protocol for Efficacy Testing on Appetite Usingan Ad Libitum Fed Rat MODEL

Sprague Dawley (SD) rats from Taconic Europe, Denmark are used for theexperiments. The rats have a body weight 200-250 g at the start ofexperiment. The rats arrive at least 10-14 days before start ofexperiment to allow acclimatization to experimental settings. Duringthis period the animals are handled at least 2 times. After arrival ratsare housed individually for one week in a reversed light/dark phase(meaning that lights are off during daytime and on during nighttime) fortwo weeks. Since rats are normally active and eat their major part oftheir daily food intake during the dark period, rats are dosed in themorning right before lights are turned off. This set-up results in thelowest data variation and highst test sensitivity. The experiment isconducted in the rats' home cages and rats have free access to food andwater throughout the acclimatization period and the experiment period.Each dose of derivative is tested in a group of 5-8 rats. A vehiclegroup of 6-8 rats is included in each set of testing. Rats are dosedonce according to body weight with a 0.01-3 mg/kg solution administeredintraperitoneally (ip), orally (po) or subcutaneously (sc). The time ofdosing is recorded for each group. After dosing, the rats are returnedto their home cages, where they then have access to food and water. Thefood consumption is recorded individually continuously by onlineregistration or manually every hour for 7 hours, and then after 24 h andsometimes 48 h. At the end of the experimental session, the animals areeuthanized.

The individual data are recorded in Microsoft excel sheets. Outliers areexcluded after applying the Grubbs statistical evaluation test foroutliers, and the result is presented graphically using the GraphPadPrism program.

Assay (II)—Functional Assays Assay (II)a—Human Calcitonin and AmylinReceptor Assay 1. Luciferase Assay Outline

Activation of calcitonin and amylin (coexpression of calcitonin receptorand receptor activity modifying proteins (RAMP)) receptors lead toincreased intracellular concentrations of cAMP. Consequently,transcription is activated by promoters containing multiple copies ofthe cAMP response element (CRE). It is thus possible to measure amylinactivity by the use of a CRE luciferase reporter gene introduced intoBHK cells also expressing calcitonin or amylin receptors.

2. Construction of Calcitonin (a)- and Amylin 3(a)-Receptor/CRE-Luc CellLine.

A BHK570 cell line was stably transfected with the human calcitoninreceptor and a CRE-responsive luciferase reporter gene. The cell linewas further transfected with RAMP-3, using standard methods. This turnsthe calcitonin receptor into an amylin 3(a) receptor. Methotrexate,Neomycin, and Hygromycin are selection markers for luciferase, thecalcitonin receptor, and RAMP-3, respectively.

3. Luciferase Assays

To perform activity assays, BHK calcitonin (a) receptor- or amylin3(a)-receptor/CRE-luc cells were seeded in white 96 well culture platesat a density of about 20.000 cells/well. The cells were in 100 μl growthmedium (DMEM with 10% FBS, 1% Pen/Strep, 1 mM Na-pyruvate, 250 nMMethotrexate, 500 μg/ml Neomycin, and 400 μg/ml Hygromycin). Afterincubation overnight at 37° C. and 5% CO₂, the growth medium wasreplaced by 50 μl/well assay medium (DMEM (without phenol red),Glutamax™, 10% FBS, and 10 mM Hepes, pH 7.4). Further, 50 μl/well ofstandard or sample in assay buffer were added. After 3 hours incubationat 37° C. and 5% CO₂, the assay medium with standard or sample wereremoved and replaced by 100 μl/well PBS. Further, 100 μl/well LucLite™was added. The plates were sealed and incubated at room temperature for30 minutes. Finally, luminescence was measured on a TopCounter (Packard)in SPC (single photon counting) mode.

Assay (II)b—Rat Calcitonin and Rat Amylin Receptor Assays

cAMP Assay Outline

Activation of calcitonin and amylin (coexpression of calcitonin receptorand receptor activity modifying proteins (RAMP)) receptors lead toincreased intracellular concentrations of cAMP. In order to quantify thecAMP levels in transiently transfected cells the Adenylyl CyclaseActivation FlashPlate® Assay from Perkin Elmer was used. The basicprinciple of the FlashPlate® Assay is a competition between radioactiveand non-radioactive cAMP generated by the cells for a fixed number ofbinding sites.

Construction of Rat Calcitonin(a)- and Rat Amylin 3(a)-Receptor Cells.BHK tk′ts 13 cells were transiently transfected with either ratcalcitonin (a) receptor or amylin 3 (a) receptor (rat calcitonin(a)receptor+rat RAMP3) using FuGENE® 6 (Roche), according to themanufacturers recommendations.cAMP assay

24 hours after transient transfection the cells (rat calcitonin(a)- orrat amylin 3(a)-receptor cells) were added (100.000 cells/well) to the96 well FlashPlates® with samples or standard in FlashPlate stimulationbuffer with IBMX and incubated for 30 min. Detection mix was createdaccording to manufacturers protocol and scintillation measured after 3 hof incubation on TopCounter™ (Packard).

Assay (III)—ThT Fibrillation Assays for the Assessment of PhysicalStability of Protein Formulations

Low physical stability of a polypeptide may lead to amyloid fibrilformation, which is observed as well-ordered, thread-like macromolecularstructures in the sample eventually resulting in gel formation. This hastraditionally been measured by visual inspection of the sample. However,that kind of measurement is very subjective and depending on theobserver. Therefore, the application of a small molecule indicator probeis much more advantageous. Thioflavin T (ThT) is such a probe and has adistinct fluorescence signature when binding to fibrils [Naiki et al.(1989) Anal. Biochem. 177, 244-249; LeVine (1999) Methods. Enzymol. 09,274-284].

The time course for fibril formation can be described by a sigmoidalcurve with the following expression [Nielsen et al. (2001) Biochemistry40, 6036-6046];

$\begin{matrix}{F = {f_{i} + {m_{i}t} + \frac{f_{f} + {m_{f}t}}{1 + ^{- {\lbrack{{({t - t_{0}})}/\tau}\rbrack}}}}} & {{Eq}.\mspace{14mu} (1)}\end{matrix}$

Here, F is the ThT fluorescence at the time t. The constant t_(o) is thetime needed to reach 50% of maximum fluorescence. The two importantparameters describing fibril formation are the lag-time calculated byt₀−2τ and the apparent rate constant k_(app)=1/τ.

Formation of a partially folded intermediate of the polypeptide issuggested as a general initiating mechanism for fibrillation. Few ofthose intermediates nucleate to form a template onto which furtherintermediates may assembly and the fibrillation proceeds. The lag-timecorresponds to the interval in which the critical mass of nucleus isbuilt up and the apparent rate constant is the rate with which thefibril itself is formed.

Sample Preparation

Samples were prepared freshly before each assay. Each sample compositionis described in each example. The pH of the sample was adjusted to thedesired value using appropriate amounts of concentrated NaOH and HClO₄or HCl. Thioflavin T was added to the samples from a stock solution inH₂O to a final concentration of 1 μM.

Sample aliquots of 200 μl were placed in a 96 well microtiter plate(Packard OptiPlate™96, white polystyrene). Usually, four or eightreplica of each sample (corresponding to one test condition) were placedin one column of wells. The plate was sealed with Scotch Pad (Qiagen).

Incubation and Fluorescence Measurement

Incubation at given temperature, shaking and measurement of the ThTfluorescence emission were done in a Fluoroskan Ascent FL fluorescenceplatereader or Varioskan platereader (Thermo Labsystems). Thetemperature was adjusted to 37° C. The orbital shaking was adjusted to960 rpm with an amplitude of 1 mm in all the presented data.Fluorescence measurement was done using excitation through a 444 nmfilter and measurement of emission through a 485 nm filter.

Each run was initiated by incubating the plate at the assay temperaturefor 10 min. The plate was measured every 20 minutes for a desired periodof time. Between each measurement, the plate was shaken and heated asdescribed.

Data Handling

The measurement points were saved in Microsoft Excel format for furtherprocessing and curve drawing and fitting was performed using GraphPadPrism. The background emission from ThT in the absence of fibrils wasnegligible. The data points are typically a mean of four or eightsamples and shown with standard deviation error bars. Only data obtainedin the same experiment (i.e. samples on the same plate) are presented inthe same graph ensuring a relative measure of fibrillation betweenexperiments.

The data set may be fitted to Eq. (1). However, since full sigmodialcurves in this case are not always achieved during the measurement time,the degree of fibrillation is expressed as ThT fluorescence tabulated asthe mean of the samples and shown with the standard deviation at varioustime points.

Measurement of Initial and Final Concentrations

The polypeptide concentration in each of the tested formulations weremeasured both before application in the ThT fibrillation assay(“Initial”) and after completion of the ThT fibrillation (“After ThTassay”). Concentrations were determined by reverse HPLC methods using apramlintide standard as a reference. Before measurement after completion150 μl was collected from each of the replica and transferred to anEppendorf tube. These were centrifuged at 30000 G for 40 mins. Thesupernatants were filtered through a 0.22 μm filter before applicationon the HPLC system.

Assay (IV)—Determination of Solubility

The polypeptide was dissolved in water at −500 nmol/ml and mixed 1:1with a series of buffers (100 mM glycylglycine pH 3.0, 100 mMglycylglycine pH 4.0, 100 mM glycylglycine pH 5.0, 100 mM bistrispropanepH 6.0, 100 mM bistrispropane pH 6.5, 100 mM bistrispropane pH 7.0, 100mM bistrispropane pH 7.5, 100 mM bistrispropane pH 8.0). After 18 hoursat room temperature the samples were centrifuged and the polypeptideconcentration determined by UPLC.

Assay (V)—Determination of Binding to the Human Amylin Receptor

The binding assay was performed using scintillation proximity assay(SPA) beads (RPNQ0001) from PerkinElmer and cell membranes from theAmylin 3(a)/CRE-luc cells (as described in Assay (II)) were used.Membranes were prepared in the following way; the cells were rinsed withPBS and incubated with Versene for approximately 5 min beforeharvesting. The cells were flushed with PBS and the cell-suspension wascentrifuged for 5 min at 1000 rpm. Cells were homogenized (ultrathurrax)in a buffer containing 20 mM Na-HEPES and 10 mM EDTA (pH 7.4) andcentrifuged at 20.000 rpm for 15 min. The resulting pellet wasresuspended, homogenized and centrifuged (20.000 rpm, 15 min) in abuffer containing 20 mM Na-HEPES and 0.1 mM EDTA (pH 7.4, buffer 2). Theresulting pellet was resuspended in buffer 2 and protein concentrationwas measured (BCA protein Assay, Pierce). The homogenate was kept coldduring the whole procedure. The membranes were kept at −80° C. untiluse. The assay was performed in a 384 well Optiplate (PerkinElmer) in atotal volume of 40 ul. Membranes were mixed with SPA beads. Finalconcentration of membranes 35 ng/μL final and SPA beads was 0.05mg/well. Test-compounds were dissolved in DMSO and further diluted inassay buffer (50 mM Hepes, pH 7.4, 1 mM CaCl2, 5 mM MgCl₂, 0.1% OA and0.02% Tween20). Radioligand ¹²⁵I-rat amylin (NEX448 PerkinElmer) wasdissolved in assay buffer and added to the Optiplate at a finalconcentration of 50 pM/well (approx. 20.000 cpm/10 ul). The finalmixture was incubated with shaking at 400 rpm for 120 min at 25° C.prior to centrifugation (1500 rpm, 10 min). Samples were analyzed onTopCounter™ (Packard). The IC₅₀ was calculated using (one site bindingcompetition analysis) GraphPad Prism5 as a measure of receptor affinity.

Assay (VI)—Determination of the Binding to the Rat Amylin Receptor

The assay was performed as described above (Assay (V)—Determination ofbinding to the human amylin receptor) with the exception that we usedmembranes prepared from BHK tk′ts 13 cells that were transientlytransfected with the rat calcitonin receptor rat RAMP 3 at an equimolarratio (1:2). The BHK tk′ts 13 cells were transiently transfected withrat calcitonin receptor using FuGENE® 6 (Roche), according to themanufacturer's recommendations. Cells were grown in DMEM with 10% FBSand 1% Pen/Strep. Approximately 48 hours after transfection, the cellswere harvested and membranes were prepared.

Assay (VII)—Determination of binding to the human calcitonin receptor

The binding assay was performed using scintillation proximity assay(SPA) beads (RPNQ0001) from PerkinElmer and cell membranes prepared froma BHK tk′ts 13 cell line was stably transfected with the humancalcitonin receptor and a CRE-responsive luciferase reporter gene.Membranes were prepared in the following way; the cells were rinsed withPBS and incubated with Versene for approximately 5 min beforeharvesting. The cells were flushed with PBS and the cell-suspension wascentrifuged for 5 min at 1000 rpm. Cells were homogenized (Ultrathurrax)in a buffer containing 20 mM Na-HEPES and 10 mM EDTA (pH 7.4) andcentrifuged at 20.000 rpm for 15 min. The resulting pellet wasresuspended, homogenized and centrifuged (20.000 rpm, 15 min) in abuffer containing 20 mM Na-HEPES and 0.1 mM EDTA (pH 7.4, buffer 2). Theresulting pellet was resuspended in buffer 2 and protein concentrationwas measured (BCA protein Assay, Pierce). The homogenate was kept coldduring the whole procedure. The membranes were kept at −80° C. untiluse. Assay was performed in a 384 well Optiplate (PerkinElmer) in atotal volume of 40 ul. Membranes were mixed with SPA beads. Finalconcentration of membranes 35 ng/μL final and Final concentration of SPAbeads was 0.05 mg/well. Test-compounds were dissolved in DMSO andfurther diluted in assay buffer (50 mM Hepes, pH 7.4, 1 mM CaCl2, 5 mMMgCl₂, 0.1% OA and 0.02% Tween20). Radioligand ¹²⁵I-Calcitonin (NEX422PerkinElmer) was dissolved in assay buffer and added to the Optiplate ata final concentration of 75 pM/well (approx. 30.000 cpm/10 ul). Thefinal mixture was incubated for 120 min with shaking at 400 rpm at 25°C. prior to centrifugation (1500 rpm, 10 min). Samples were analyzed onTopCounter™ (Packard). The 10₅₀ was calculated using (one site bindingcompetition analysis) GraphPad Prism5 as a measure of receptor affinity.

Assay (VIII)—Determination of Binding to the Rat Calcitonin Receptor

The assay was performed as described above (Assay (VII)—Determination ofbinding to the human calcitonin receptor) with the exception that weused membranes prepared from BHK tk′ts 13 cells that were transientlytransfected with the rat calcitonin receptor. The BHK tk′ts 13 cellswere transiently transfected with rat calcitonin receptor using FuGENE®6 (Roche), according to the manufacturer's recommendations. Cells weregrown in DMEM with 10% FBS and 1% Pen/Strep. Approximately 48 hoursafter transfection, the cells were harvested and membranes wereprepared.

Assay (IX)—pK—Determination of T1/2 in Mini-Pig

T½ is the terminal half-life=ln 2/λ_(z) of a compound in plasma. λ_(z)is the first order rate constant associated with the terminal(log-linear) portion of the plasma concentration-time curve and isestimated by linear regression of time vs. log concentration.

T½ values of the amylin analogues of the invention is determined bypharmacokinetic studies in male Göttingen mini-pigs from EllegaardGöttingen Minipigs ApS and the principles of laboratory animal care arefollowed.

An acclimatisation period of approximately 6-10 days was allowed beforethe animals entered the study. At start of the acclimatisation periodthe mini-pigs were about 5 to 12 months old and in the weight range of7-35 kg. The mini-pigs had two central venous catheters inserted whichwere used for blood sampling.

The studies were conducted in an animal room which was illuminated togive a cycle of approx 12 hours light and 12 hours darkness. The animalswere housed individually.

The animals had free access to domestic quality drinking water duringthe study, but were typically fasted from overnight before dosing untilapprox 6-12 hours after dosing. The animals were weighed on arrival andon the days of dosing.

In the present studies the test substances were administeredsubcutaneously in approx 2 nmol/kg dose. The animals received a singlesubcutaneous injection. The subcutaneous injection was given on theright side of the neck, approximately 5-7 cm from the ear and 7-9 cmfrom the middle of the neck. The injections were given with a stopper onthe needle, allowing approx 0.5 cm of the needle to be introduced. Eachtest substance was given to typically three but in some cases two orfour animals.

A full plasma concentration-time profile, employing 12-16 samplingpoints, was obtained from each animal. In example blood samples werecollected according to the following schedule: After subcutaneousadministration:

-   -   Predose (0), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168        and 240 hours after injection.

In some cases also additional blood samples up to 288 hours postinjection were taken.

At each sampling time, 0.5 to 2 ml of blood was drawn from each animal.The blood samples were taken via the central venous catheter.

The blood samples were collected into EDTA test tubes (i.e. SarstedtMicro tube 1.3 mL K3E). Blood samples were kept on ice for max 20 min.before centrifugation. Plasma was separated using centrifugation (i.e.at 4° C., 10 min., 1500 G) and was immediately transferred to Micronictubes. Approximately 200 μl plasma was transferred to each Micronictube. The plasma was stored at −20° C. until assayed. The plasma sampleswere assayed for the content of amylin using an ELISA assay.

The plasma concentration-time profiles were analysed by anon-compartmental pharmacokinetic analysis (NCA) using WinNonlinProfessional 5.0 (Pharsight Inc., Mountain View, Calif., USA). NCA wasperformed using the individual plasma concentration-time profiles fromeach animal. T½ is the terminal half-life=ln 2/λ_(z) and was determinedfrom A_(z) the first order rate constant associated with the terminal(log-linear) portion of the curve, estimated by linear regression oftime vs. log concentration.

ELISA Plasma Assay for Amylin Quantification

The human amylin ELISA is a monoclonal antibody-based sandwichimmunoassay for determining amylin levels in human plasma. The captureantibody recognizes human amylin, amylin acid (deamidated amylin), a1-20 fragment of amylin, but not reduced amylin. The detection antibodybinds to reduced or unreduced human amylin but not amylin acid and iscomplexed with streptavidin-alkaline phosphatase. The substrate,4-methylumbelliferyl phosphate, is applied to the completed sandwich andthe fluorescent signal, monitored at 355 nm/460 nm, is proportional tothe amount of amylin present in the sample.

MS-Method for Amylin Quantification

40 μl plasma is diluted with 120 μl 66.67% EtOH+1% HCOOH and mixed.Centrifuged for 20 min. at 13000 rpm, 4° C. The supernatant is analyzedby an LC-MS method on a Sciex API 3000 and quantitated with a standardmade up in plasma

Assay (X)—pK—Determination of T½ in Rat

T½ is the terminal half-life=ln 2/λ_(z) of a compound in plasma. λ_(z)is the first order rate constant associated with the terminal(log-linear) portion of the plasma concentration-time curve and isestimated by linear regression of time vs. log concentration.

T½ values of the amylin analogues of the invention is determined bypharmacokinetic studies in Sprague Dawley male rats, from Taconic Europeand the principles of laboratory animal care are followed.

An acclimatisation period of approximately 7 days was allowed before theanimals entered the study. At start of the acclimatisation period therats were in the weight range of 300-400 g. The rats had permanentcatheters inserted in a. carotis which were used for blood sampling.

The studies were conducted in an animal room which was illuminated togive a cycle of approx 12 hours light and 12 hours darkness. The animalswere housed individually due to the catheters and had food and water adlib. The animals were weighed on the days of dosing.

In the present studies the test substances were administeredsubcutaneously in approx 20 nmol/kg dose. The animals received a singlesubcutaneous injection to the neck using a 25 G needle with syringe.Each test substance was given to typically three but in some cases twoor four animals.

A full plasma concentration-time profile, employing 8-10 samplingpoints, was obtained from each animal. In example blood samples werecollected according to the following schedule: After subcutaneousadministration:

-   -   Predose (0), 0.5, 1, 1.5, 2, 4, 6, 12, 24, 48 and 72 hours after        injection.

At each sampling time, 0.08 to 0.10 ml of blood was drawn from eachanimal. The blood samples were taken via the catheter.

The blood samples were collected into EDTA test tubes. Blood sampleswere kept on ice for max 20 min. before centrifugation. Plasma wasseparated using centrifugation (i.e. at 4° C., 10 min., 1500 G) and wasimmediately transferred to Micronic tubes or PCR plates. Approximately40 μl plasma was transferred and was stored at −20° C. until assayed.The plasma samples were assayed for the content of amylin using an ELISAassay.

The plasma concentration-time profiles were analysed by anon-compartmental pharmacokinetic analysis (NCA) using WinNonlinProfessional 5.0 (Pharsight Inc., Mountain View, Calif., USA). NCA wasperformed using the individual plasma concentration-time profiles fromeach animal. T½ is the terminal half-life=ln 2/λ_(z) and was determinedfrom λ_(z) the first order rate constant associated with the terminal(log-linear) portion of the curve, estimated by linear regression oftime vs. log concentration.

Assay (XI)—Effect from Single Subcutaneous Administration of Analogue onPlasma Calcium in Rats

Male Sprague-Dawley rats (Taconic Europe, ˜250 g at test date) wereacclimatized to reversed day light cycle (lights on from 10 PM to 10 AM)and single housing in online food intake monitoring system (EllegaardMBRose, Denmark) prior to study start. Rats were divided in groups offive and subcutaneously dosed with test compound (30 nmol/kg) and foodintake was monitored for 48 hours hereafter. Data are illustrated ingraphs as mean±SEM. Reduction of food intake from administration of thecompound is positively correlated to the binding of the compound to theamylin receptor.

Assay (XII)—Effect from Single Subcutaneous Administration of Analogueon Plasma Calcium in Rats

Male Wistar rats (Taconic Europe, ˜250 g at test date) were acclimatizedto handling prior to the study. Rats were divided in groups of five andsubcutaneously dosed with test compound at time=0. At time T=−15 min; 1h, 2 h, 4 h, 7 h, 12 h, and 24 h a blood sample was obtained and heparinstabilized plasma was analysed for total calcium (Cobas, Hitachi). Dataare illustrated in graphs as mean±SEM.

Preparations

The polypeptide sequences were prepared according to the below-mentionedpolypeptide synthesis and the compounds as presented in the Tables (e.g.Table 2 or Table 3) were prepared according to the below-mentionedsynthesis.

One method of polypeptide synthesis was by Fmoc chemistry on amicrowave-based Liberty polypeptide synthesizer (CEM Corp., NorthCarolina). The resin was Tentagel S RAM with a loading of about 0.25mmol/g or PAL-ChemMatrix with a loading of about 0.43 mmol/g. Thecoupling chemistry was DIC/HOAt in NMP using amino acid solutions of 0.3M in NMP and a molar excess of 6-8 fold. Coupling conditions was 5minutes at up to 70° C. Deprotection was with 5% piperidine in NMP at upto 70° C. The protected amino acids used were standard Fmoc-amino acids(supplied from e.g. Anaspec or Novabiochem) dissolved at 0.3 M in NMPcontaining 0.3 M HOAt.

Another method of polypeptide synthesis was by Fmoc chemistry on aPrelude polypeptide synthesizer (Protein Technologies, Arizona). Theresin was Tentagel S RAM with a loading of about 0.25 mmol/g or PAL-ChemMatrix with a loading of about 0.43 mmol/g. The coupling chemistry wasDIC/HOAt in NMP using amino acid solutions of 0.3 M in NMP and a molarexcess of 6-8 fold. Coupling conditions was single or double couplingsfor 1 or 2 hours at room temperature. Deprotection was with 20%piperidine in NMP. The protected amino acids used were standardFmoc-amino acids (supplied from e.g. Anaspec or Novabiochem) dissolvedat 0.3 M in NMP containing 0.3 M HOAt.

Another method of polypeptide synthesis was on an Applied Biosystems 433polypeptide synthesizer in 0.25 mmol or 1.0 mmol scale using themanufacturer supplied FastMoc UV protocols which employ HBTU or HATUmediated couplings in NMP, and UV monitoring of the deprotection of theFmoc protection group. The starting resin used for the synthesis of thepolypeptide amides was Rink-Amide resin. The protected amino acidderivatives used were standard Fmoc-amino acids (supplied from e.g.Anaspec, or Novabiochem) supplied in preweighed cartridges suitable forthe AB1433A synthesizer.

When a chemical modification of a lysine side chain was desired, thelysine was incorporated as Lys(Mtt) and the N-terminal amino acid waseither incorporated into the sequence as a Boc-amino acid or, if theN-terminal amino acid was incorporated as an Fmoc-amino acid, the Fmocgroup was removed and the N-terminal was protected by treatment with 6equivalents of Boc-carbonate and 6 equivalents of DIPEA in NMP for 30minutes. The resin was washed with NMP and DCM and the Mtt group wasremoved by suspending the resin in neat hexafluoroisopropanol for 20minutes followed by washing with DCM and NMP. The chemical modificationof the lysine was performed by adding one or more of the building blockslisted below by the same methods as used for the polypeptide synthesis,i.e. by one or more automated steps on the Liberty or the ABI 433 or byone or more manual coupling steps at room temperature. After synthesisthe resin was washed with DCM and dried, and the polypeptide was cleavedfrom the resin by a 2 hour treatment with TFA/TIPS/water (92.5/5/2.5 or95/2.5/2.5) followed by precipitation with 4 volumes of diethylether,further washing with diethylether and drying. If the polypeptidecontained cysteines protected with Acm groups, the polypeptide wasredissolved in water at 2-5 mg/ml, pH adjusted to below 4, and thedisulfide bridge formed by treatment with 4 eq. of iodine (2% w/v inmethanol) for 15 minutes. Alternatively, the disulfide bridge was formedon the resin by using Trt as the protecting group for cysteine andtreating with 10 equivalents of iodine in NMP for 1 hour. In this casethe crude polypeptide was purified directly after cleavage anddiethylether precipitation.

Purification: The crude polypeptide was purified by semipreparative HPLCon a 20 mm×250 mm column packed with either 5μ or 7μ C-18 silica.Polypeptide solutions were pumped onto the HPLC column and precipitatedpolypeptides were dissolved in 5 ml 50% acetic acid H₂O and diluted to20 ml with H₂O and injected on the column which then was eluted with agradient of 40-60% CH₃CN in 0.1% TFA 10 ml/min during 50 min at 40° C.The polypeptide containing fractions were collected. The purifiedpolypeptide was lyophilized after dilution of the eluate with water.

For analysis of HPLC-fractions and final product RP-HPLC analysis wasperformed using UV detection at 214 nm and e.g. a Vydac 218TP54 4.6mm×250 mm 5μ C-18 silica column (The Separations Group, Hesperia, USA)and eluted at e.g. 1 ml/min at 42° C. Most often one of four differentelution conditions was used:

A1: Equilibration of the column with a buffer consisting of 0.1 M(NH₄)₂SO₄, which was adjusted to pH 2.5 with concentrated H₂SO₄ andelution by a gradient of 0% to 60% CH₃CN in the same buffer during 50min.

B1: Equilibration of the column with 0.1% TFA/H₂O and elution by agradient of 0% CH₃CN/0.1% TFA/H₂O to 60% CH₃CN/0.1% TFA/H₂O during 50min.

B6: Equilibration of the column with 0.1% TFA/H₂O and elution by agradient of 0% CH₃CN/0.1% TFA/H₂O to 90% CH₃CN/0.1% TFA/H₂O during 50min.

Alternatively the RP-HPLC analysis was performed using UV detection at214 nm and a Symmetry300, 3.6 mm×150 mm, 3.5 g C-18 silica column(Waters) which was eluted at 1 ml/min at 42° C.

B4: Equilibration of the column with 0.05% TFA/H₂O and elution by agradient of 5% CH₃CN/0.05% TFA/H₂O to 95% CH₃CN/0.05% TFA/H₂O during 15min.

The identity of the polypeptide was confirmed by MALDI-MS on a BrukerMicroflex.

The polypeptides prepared are shown in Table 2 (presented earlier):

Binding to Human Amylin Receptors

The in vitro data regarding binding to human amylin receptors are shownin Table 4 (below). Table 4 discloses compounds that have a hAmylinRIC50 value of less than 1200 pM. Details of the albumin binding moiety,linker and acylation sites have been removed from these Tables. For fullstructural information please consult the entry with a correspondingcompound number in Table 2. Further details regarding the compounds,such as IUPAC nomenclature may be found in Table 14.

TABLE 4 Example hAmylin-R bind IC50 no. Sequence modifications (pM) 114D, 17R, 21P, 26P, 35D 1177 2 14D, 17R, 21P, 27P, 35D 411 3 14D, 17R,22P, 26P, 35D 1131 4 14E, 17R, 21P, 25P, 28P, 29P, 37P 321 5 14E, 17R,21P, 26P, 37P 374 6 14E, 17R, 21P, 25P, 28P, 29P 996 7 14E, 17R, 21P,26P 674 8 14E, 17R, 21P, 27P, 37P 72 9 14E, 17R, 21P, 27P 143 10 14D,17R, 21P, 27P, 37P 82 11 14E, 17R, 21P, 27P, 35D, 37P 105 12 14E, 17R,21P, 27P, 37P 142 13 14E, 17R, 21P, 27P, 37P 264 14 14E, 17R, 21P, 27P,37P 196 15 14E, 17R, 21P, 27P 597 16 14E, 17R, 21P, 27P, 35R 894 17 14E,17R, 21P, 27P, 34H 878 18 14E, 17R, 21P, 27P, 35H 554 19 14E, 17R, 21P,27P 556 20 14E, 17R, 21P, 27P, 37P 217 21 17R, 21P, 27P 585 22 14E, 17R,21P, 27P, 35E 794 23 17R, 21P, 27P, 35E 871 24 17R, 21P, 27P 1138 2517R, 21P, 27P, 35E 768 26 17R, 21P, 27P, 35E 532 27 17R, 21P, 27P, 35E837 28 17R, 21P, 27P, 31P, 35E 610 29 17R, 21P, 27P, 34P, 35E 577 3014H, 17R, 21P, 27P, 35E 919 31 14E, 17R, 21P, 27P, 31P 204 32 14E, 17R,21P, 27P, 34P 100 33 14E, 17R, 21P, 28P, 35E 915 34 17R, 21P, 27P, 35K1139 35 17R, 21P, 27P, 35K 970 36 14E, 17R, 21P, 27P, 34K 403 37 14E,17R, 21P, 27P, 29P 970 38 17R, 21P, 27P, 35R 249 39 17R, 21P, 27P, 34R665 40 17R, 21P, 27P, 34H 549 41 17R, 21P, 27P 427 42 17R, 21P, 27P 26443 17R, 21P, 27P 76 44 −1K, 1R, 17R, 21P, 27P, 35H 275 45 −1K, 1R, 17R,21P, 27P, 35H 552 46 −1G, 1R, 17R, 21P, 27P 195 47 −1G, 1R, 17R, 21P,27P, 35H 344 48 17R, 21P, 27P 443 49 17R, 21P, 27P, 31P 1191 50 17R,21P, 27P, 34P 38 51 14E, 17R, 21P, 27P, 35R 828 52 14D, 17R, 21P, 27P,35R 697 53 17R, 21P, 27P, 28P, 31P 52 54 17R, 21P, 27P, 29P, 31P 30 5517R, 21P, 27P, 28P, 34P 42 56 17R, 21P, 27P, 29P, 34P 49 57 17R, 21P,27P, 31P, 35H 115 58 17R, 21P, 27P, 34P, 35H 88 59 14D, 17R, 21K, 27P,35D 1193 60 17R, 21P, 27P, 35H 695 61 14H, 17R, 21P, 27P, 31P 122 6214H, 17R, 21P, 27P, 31P 98 63 14R, 17R, 21P, 27P, 31P 825 64 14R, 17R,21P, 27P, 31P 444 65 14R, 17R, 21P, 27P, 34P 649 66 14H, 17R, 21P, 27P,35H 396 67 14H, 17R, 21P, 27P, 34P 90 68 14H, 17R, 21P, 27P, 34P 88 6914H, 17R, 21P, 27P 133 70 14H, 17R, 21P, 27P 169 71 14G, 17R, 21P, 27P,31P 48 72 14A, 17R, 21P, 27P, 31P 172 73 14S, 17R, 21P, 27P, 31P 104 7414K, 17R, 21P, 27P, 31P 791 75 14T, 17R, 21P, 27P, 31P 666 76 17R, 21P,27P, 34H 215 77 17R, 21P, 27P, 34H 428 78 17R, 21P, 27P, 34R 602 79 17R,21P, 27P, 34R 790 80 14H, 17R, 21P, 27P, 34H 290 81 14H, 17R, 21P, 27P,34H 271 82 14R, 17R, 21P, 27P 636 83 14R, 17R, 21P, 27P 939 84 14H, 17R,21P, 27P, 34R 743 85 14H, 17R, 21P, 27P, 34R 876 86 17R, 21P, 27P, 34H833 87 14E, 17R, 21P, 27P, 34H 633 88 14E, 17R, 21P, 27P, 34R 750 8914E, 17R, 21P, 27P, 35R 1160 90 14H, 17R, 21P, 27P 61 91 17R, 21P, 27P,34H 119 92 14H, 17R, 21P, 27P 179 93 14A, 17R, 21P, 27P, 34H 176 94 14A,17R, 21P, 27P, 34P 148 95 17R, 21P, 27P, 34R 967 96 17R, 21P, 27P, 31P166 97 17R, 21P, 27P, 34H 568 98 17R, 21P, 27P, 34P 91 99 −1G, 1R, 14H,17R, 21P, 27P 348 100 −1G, 1R, 14H, 17R, 21P, 27P, 34H 1015 101 −1G, 1R,14A, 17R, 21P, 27P, 34H 426 102 −1G, 1R, 14H, 17R, 21P, 27P, 34P 217 103−1G, 1R, 14A, 17R, 21P, 27P, 34P 114 104 14E, 17R, 21P, 27P, 34H, 35E525 105 14E, 17R, 21P, 27P, 34R, 35E 957 106 14E, 17R, 21P, 27P, 34P,35E 121 107 14E, 17R, 21P, 27P, 34H, 35E 387 108 14E, 17R, 21P, 27P,34R, 35E 232 109 14E, 17R, 21P, 27P, 34P, 35E 140 110 14E, 17R, 21P,27P, 34P, 35R 326 111 17R, 21P, 27P, 34H 580 112 17R, 21P, 27P, 34H 1037113 17R, 21P, 27P, 34H 382 114 14E, 17R, 21P, 27P, 34P, 37P 214 115 14H,17R, 21P, 27P, 34P, 37P 131 116 14H, 17R, 21P, 27P, 31P, 34P 82 117 14E,17R, 21P, 27P, 34P, 35R 163 118 14E, 17R, 21P, 27P, 34P, 35H 179 11917R, 21P, 27P, 31P, 34P, 35R 880 120 14S, 17R, 21P, 27P, 34P, 35E 76 12114E, 17R, 21P, 31P, 34P, 35E 69 122 14D, 17R, 21P, 27P, 34P, 35E 172 12314D, 17R, 21P, 27P, 34P, 35E 196 124 14E, 17R, 21P, 27P, 34P, 35H 377125 14E, 17R, 21P, 27P, 34P, 35E, 37P 533 126 14E, 17R, 23P, 34P, 35E1187 127 14E, 17R, 21P, 27P, 34P, 37F 152 128 14E, 17R, 21P, 27P, 35H992 129 14D, 17R, 21P, 27P, 34P, 35R 281 130 14D, 17R, 21P, 27P, 34P,35R 453 131 14d, 17R, 21P, 27P, 35R 365 132 14D, 17R, 21P, 27P, 35R 266

TABLE 4a Example hAmylin-R bind IC50 no. Sequence modifications (pM) 214D, 17R, 21P, 27P, 35D 411 4 14E, 17R, 21P, 25P, 28P, 29P, 37P 321 514E, 17R, 21P, 26P, 37P 374 6 14E, 17R, 21P, 25P, 28P, 29P 996 7 14E,17R, 21P, 26P 674 8 14E, 17R, 21P, 27P, 37P 72 9 14E, 17R, 21P, 27P 14310 14D, 17R, 21P, 27P, 37P 82 11 14E, 17R, 21P, 27P, 35D, 37P 105 1214E, 17R, 21P, 27P, 37P 142 13 14E, 17R, 21P, 27P, 37P 264 14 14E, 17R,21P, 27P, 37P 196 15 14E, 17R, 21P, 27P 597 16 14E, 17R, 21P, 27P, 35R894 17 14E, 17R, 21P, 27P, 34H 878 18 14E, 17R, 21P, 27P, 35H 554 1914E, 17R, 21P, 27P 556 20 14E, 17R, 21P, 27P, 37P 217 21 17R, 21P, 27P585 22 14E, 17R, 21P, 27P, 35E 794 23 17R, 21P, 27P, 35E 871 25 17R,21P, 27P, 35E 768 26 17R, 21P, 27P, 35E 532 27 17R, 21P, 27P, 35E 837 2817R, 21P, 27P, 31P, 35E 610 29 17R, 21P, 27P, 34P, 35E 577 30 14H, 17R,21P, 27P, 35E 919 31 14E, 17R, 21P, 27P, 31P 204 32 14E, 17R, 21P, 27P,34P 100 33 14E, 17R, 21P, 28P, 35E 915 35 17R, 21P, 27P, 35K 970 36 14E,17R, 21P, 27P, 34K 403 37 14E, 17R, 21P, 27P, 29P 970 38 17R, 21P, 27P,35R 249 39 17R, 21P, 27P, 34R 665 40 17R, 21P, 27P, 34H 549 41 17R, 21P,27P 427 42 17R, 21P, 27P 264 43 17R, 21P, 27P 76 44 −1K, 1R, 17R, 21P,27P, 35H 275 45 −1K, 1R, 17R, 21P, 27P, 35H 552 46 −1G, 1R, 17R, 21P,27P 195 47 −1G, 1R, 17R, 21P, 27P, 35H 344 48 17R, 21P, 27P 443 50 17R,21P, 27P, 34P 38 51 14E, 17R, 21P, 27P, 35R 828 52 14D, 17R, 21P, 27P,35R 697 53 17R, 21P, 27P, 28P, 31P 52 54 17R, 21P, 27P, 29P, 31P 30 5517R, 21P, 27P, 28P, 34P 42 56 17R, 21P, 27P, 29P, 34P 49 57 17R, 21P,27P, 31P, 35H 115 58 17R, 21P, 27P, 34P, 35H 88 60 17R, 21P, 27P, 35H695 61 14H, 17R, 21P, 27P, 31P 122 62 14H, 17R, 21P, 27P, 31P 98 63 14R,17R, 21P, 27P, 31P 825 64 14R, 17R, 21P, 27P, 31P 444 65 14R, 17R, 21P,27P, 34P 649 66 14H, 17R, 21P, 27P, 35H 396 67 14H, 17R, 21P, 27P, 34P90 68 14H, 17R, 21P, 27P, 34P 88 69 14H, 17R, 21P, 27P 133 70 14H, 17R,21P, 27P 169 71 14G, 17R, 21P, 27P, 31P 48 72 14A, 17R, 21P, 27P, 31P172 73 14S, 17R, 21P, 27P, 31P 104 74 14K, 17R, 21P, 27P, 31P 791 7514T, 17R, 21P, 27P, 31P 666 76 17R, 21P, 27P, 34H 215 77 17R, 21P, 27P,34H 428 78 17R, 21P, 27P, 34R 602 79 17R, 21P, 27P, 34R 790 80 14H, 17R,21P, 27P, 34H 290 81 14H, 17R, 21P, 27P, 34H 271 82 14R, 17R, 21P, 27P636 83 14R, 17R, 21P, 27P 939 84 14H, 17R, 21P, 27P, 34R 743 85 14H,17R, 21P, 27P, 34R 876 86 17R, 21P, 27P, 34H 833 87 14E, 17R, 21P, 27P,34H 633 88 14E, 17R, 21P, 27P, 34R 750 90 14H, 17R, 21P, 27P 61 91 17R,21P, 27P, 34H 119 92 14H, 17R, 21P, 27P 179 93 14A, 17R, 21P, 27P, 34H176 94 14A, 17R, 21P, 27P, 34P 148 95 17R, 21P, 27P, 34R 967 96 17R,21P, 27P, 31P 166 97 17R, 21P, 27P, 34H 568 98 17R, 21P, 27P, 34P 91 99−1G, 1R, 14H, 17R, 21P, 27P 348 101 −1G, 1R, 14A, 17R, 21P, 27P, 34H 426102 −1G, 1R, 14H, 17R, 21P, 27P, 34P 217 103 −1G, 1R, 14A, 17R, 21P,27P, 34P 114 104 14E, 17R, 21P, 27P, 34H, 35E 525 105 14E, 17R, 21P,27P, 34R, 35E 957 106 14E, 17R, 21P, 27P, 34P, 35E 121 107 14E, 17R,21P, 27P, 34H, 35E 387 108 14E, 17R, 21P, 27P, 34R, 35E 232 109 14E,17R, 21P, 27P, 34P, 35E 140 110 14E, 17R, 21P, 27P, 34P, 35R 326 11117R, 21P, 27P, 34H 580 113 17R, 21P, 27P, 34H 382 114 14E, 17R, 21P,27P, 34P, 37P 214 115 14H, 17R, 21P, 27P, 34P, 37P 131 116 14H, 17R,21P, 27P, 31P, 34P 82 117 14E, 17R, 21P, 27P, 34P, 35R 163 118 14E, 17R,21P, 27P, 34P, 35H 179 119 17R, 21P, 27P, 31P, 34P, 35R 880 120 14S,17R, 21P, 27P, 34P, 35E 76 121 14E, 17R, 21P, 31P, 34P, 35E 69 122 14D,17R, 21P, 27P, 34P, 35E 172 123 14D, 17R, 21P, 27P, 34P, 35E 196 12414E, 17R, 21P, 27P, 34P, 35H 377 125 14E, 17R, 21P, 27P, 34P, 35E, 37P533 127 14E, 17R, 21P, 27P, 34P, 37F 152 128 14E, 17R, 21P, 27P, 35H 992129 14D, 17R, 21P, 27P, 34P, 35R 281 130 14D, 17R, 21P, 27P, 34P, 35R453 131 14d, 17R, 21P, 27P, 35R 365 132 14D, 17R, 21P, 27P, 35R 266

TABLE 4b Example hAmylin-R bind IC50 no. Sequence modifications (pM) 214D, 17R, 21P, 27P, 35D 411 4 14E, 17R, 21P, 25P, 28P, 29P, 37P 321 514E, 17R, 21P, 26P, 37P 374 7 14E, 17R, 21P, 26P 674 8 14E, 17R, 21P,27P, 37P 72 9 14E, 17R, 21P, 27P 143 10 14D, 17R, 21P, 27P, 37P 82 1114E, 17R, 21P, 27P, 35D, 37P 105 12 14E, 17R, 21P, 27P, 37P 142 13 14E,17R, 21P, 27P, 37P 264 14 14E, 17R, 21P, 27P, 37P 196 15 14E, 17R, 21P,27P 597 18 14E, 17R, 21P, 27P, 35H 554 19 14E, 17R, 21P, 27P 556 20 14E,17R, 21P, 27P, 37P 217 21 17R, 21P, 27P 585 22 14E, 17R, 21P, 27P, 35E794 25 17R, 21P, 27P, 35E 768 26 17R, 21P, 27P, 35E 532 28 17R, 21P,27P, 31P, 35E 610 29 17R, 21P, 27P, 34P, 35E 577 31 14E, 17R, 21P, 27P,31P 204 32 14E, 17R, 21P, 27P, 34P 100 36 14E, 17R, 21P, 27P, 34K 403 3817R, 21P, 27P, 35R 249 39 17R, 21P, 27P, 34R 665 40 17R, 21P, 27P, 34H549 41 17R, 21P, 27P 427 42 17R, 21P, 27P 264 43 17R, 21P, 27P 76 44−1K, 1R, 17R, 21P, 27P, 35H 275 45 −1K, 1R, 17R, 21P, 27P, 35H 552 46−1G, 1R, 17R, 21P, 27P 195 47 −1G, 1R, 17R, 21P, 27P, 35H 344 48 17R,21P, 27P 443 50 17R, 21P, 27P, 34P 38 52 14D, 17R, 21P, 27P, 35R 697 5317R, 21P, 27P, 28P, 31P 52 54 17R, 21P, 27P, 29P, 31P 30 55 17R, 21P,27P, 28P, 34P 42 56 17R, 21P, 27P, 29P, 34P 49 57 17R, 21P, 27P, 31P,35H 115 58 17R, 21P, 27P, 34P, 35H 88 60 17R, 21P, 27P, 35H 695 61 14H,17R, 21P, 27P, 31P 122 62 14H, 17R, 21P, 27P, 31P 98 64 14R, 17R, 21P,27P, 31P 444 65 14R, 17R, 21P, 27P, 34P 649 66 14H, 17R, 21P, 27P, 35H396 67 14H, 17R, 21P, 27P, 34P 90 68 14H, 17R, 21P, 27P, 34P 88 69 14H,17R, 21P, 27P 133 70 14H, 17R, 21P, 27P 169 71 14G, 17R, 21P, 27P, 31P48 72 14A, 17R, 21P, 27P, 31P 172 73 14S, 17R, 21P, 27P, 31P 104 74 14K,17R, 21P, 27P, 31P 791 75 14T, 17R, 21P, 27P, 31P 666 76 17R, 21P, 27P,34H 215 77 17R, 21P, 27P, 34H 428 78 17R, 21P, 27P, 34R 602 79 17R, 21P,27P, 34R 790 80 14H, 17R, 21P, 27P, 34H 290 81 14H, 17R, 21P, 27P, 34H271 82 14R, 17R, 21P, 27P 636 84 14H, 17R, 21P, 27P, 34R 743 87 14E,17R, 21P, 27P, 34H 633 88 14E, 17R, 21P, 27P, 34R 750 90 14H, 17R, 21P,27P 61 91 17R, 21P, 27P, 34H 119 92 14H, 17R, 21P, 27P 179 93 14A, 17R,21P, 27P, 34H 176 94 14A, 17R, 21P, 27P, 34P 148 96 17R, 21P, 27P, 31P166 97 17R, 21P, 27P, 34H 568 98 17R, 21P, 27P, 34P 91 99 −1G, 1R, 14H,17R, 21P, 27P 348 101 −1G, 1R, 14A, 17R, 21P, 27P, 34H 426 102 −1G, 1R,14H, 17R, 21P, 27P, 34P 217 103 −1G, 1R, 14A, 17R, 21P, 27P, 34P 114 10414E, 17R, 21P, 27P, 34H, 35E 525 105 14E, 17R, 21P, 27P, 34R, 35E 957106 14E, 17R, 21P, 27P, 34P, 35E 121 107 14E, 17R, 21P, 27P, 34H, 35E387 108 14E, 17R, 21P, 27P, 34R, 35E 232 109 14E, 17R, 21P, 27P, 34P,35E 140 110 14E, 17R, 21P, 27P, 34P, 35R 326 111 17R, 21P, 27P, 34H 580113 17R, 21P, 27P, 34H 382 114 14E, 17R, 21P, 27P, 34P, 37P 214 115 14H,17R, 21P, 27P, 34P, 37P 131 116 14H, 17R, 21P, 27P, 31P, 34P 82 117 14E,17R, 21P, 27P, 34P, 35R 163 118 14E, 17R, 21P, 27P, 34P, 35H 179 12014S, 17R, 21P, 27P, 34P, 35E 76 121 14E, 17R, 21P, 31P, 34P, 35E 69 12214D, 17R, 21P, 27P, 34P, 35E 172 123 14D, 17R, 21P, 27P, 34P, 35E 196124 14E, 17R, 21P, 27P, 34P, 35H 377 125 14E, 17R, 21P, 27P, 34P, 35E,37P 533 127 14E, 17R, 21P, 27P, 34P, 37F 152 129 14D, 17R, 21P, 27P,34P, 35R 281 130 14D, 17R, 21P, 27P, 34P, 35R 453 131 14d, 17R, 21P,27P, 35R 365 132 14D, 17R, 21P, 27P, 35R 266

TABLE 4c Example hAmylin-R bind IC50 no. Sequence modifications (pM) 214D, 17R, 21P, 27P, 35D 411 4 14E, 17R, 21P, 25P, 28P, 29P, 37P 321 514E, 17R, 21P, 26P, 37P 374 8 14E, 17R, 21P, 27P, 37P 72 9 14E, 17R,21P, 27P 143 10 14D, 17R, 21P, 27P, 37P 82 11 14E, 17R, 21P, 27P, 35D,37P 105 12 14E, 17R, 21P, 27P, 37P 142 13 14E, 17R, 21P, 27P, 37P 264 1414E, 17R, 21P, 27P, 37P 196 15 14E, 17R, 21P, 27P 597 18 14E, 17R, 21P,27P, 35H 554 19 14E, 17R, 21P, 27P 556 20 14E, 17R, 21P, 27P, 37P 217 2117R, 21P, 27P 585 26 17R, 21P, 27P, 35E 532 29 17R, 21P, 27P, 34P, 35E577 31 14E, 17R, 21P, 27P, 31P 204 32 14E, 17R, 21P, 27P, 34P 100 3614E, 17R, 21P, 27P, 34K 403 38 17R, 21P, 27P, 35R 249 40 17R, 21P, 27P,34H 549 41 17R, 21P, 27P 427 42 17R, 21P, 27P 264 43 17R, 21P, 27P 76 44−1K, 1R, 17R, 21P, 27P, 35H 275 45 −1K, 1R, 17R, 21P, 27P, 35H 552 46−1G, 1R, 17R, 21P, 27P 195 47 −1G, 1R, 17R, 21P, 27P, 35H 344 48 17R,21P, 27P 443 50 17R, 21P, 27P, 34P 38 53 17R, 21P, 27P, 28P, 31P 52 5417R, 21P, 27P, 29P, 31P 30 55 17R, 21P, 27P, 28P, 34P 42 56 17R, 21P,27P, 29P, 34P 49 57 17R, 21P, 27P, 31P, 35H 115 58 17R, 21P, 27P, 34P,35H 88 61 14H, 17R, 21P, 27P, 31P 122 62 14H, 17R, 21P, 27P, 31P 98 6414R, 17R, 21P, 27P, 31P 444 65 14R, 17R, 21P, 27P, 34P 649 66 14H, 17R,21P, 27P, 35H 396 67 14H, 17R, 21P, 27P, 34P 90 68 14H, 17R, 21P, 27P,34P 88 69 14H, 17R, 21P, 27P 133 70 14H, 17R, 21P, 27P 169 71 14G, 17R,21P, 27P, 31P 48 72 14A, 17R, 21P, 27P, 31P 172 73 14S, 17R, 21P, 27P,31P 104 76 17R, 21P, 27P, 34H 215 77 17R, 21P, 27P, 34H 428 78 17R, 21P,27P, 34R 602 80 14H, 17R, 21P, 27P, 34H 290 81 14H, 17R, 21P, 27P, 34H271 82 14R, 17R, 21P, 27P 636 87 14E, 17R, 21P, 27P, 34H 633 88 14E,17R, 21P, 27P, 34R 750 90 14H, 17R, 21P, 27P 61 91 17R, 21P, 27P, 34H119 92 14H, 17R, 21P, 27P 179 93 14A, 17R, 21P, 27P, 34H 176 94 14A,17R, 21P, 27P, 34P 148 96 17R, 21P, 27P, 31P 166 97 17R, 21P, 27P, 34H568 98 17R, 21P, 27P, 34P 91 99 −1G, 1R, 14H, 17R, 21P, 27P 348 101 −1G,1R, 14A, 17R, 21P, 27P, 34H 426 102 −1G, 1R, 14H, 17R, 21P, 27P, 34P 217103 −1G, 1R, 14A, 17R, 21P, 27P, 34P 114 104 14E, 17R, 21P, 27P, 34H,35E 525 105 14E, 17R, 21P, 27P, 34R, 35E 957 106 14E, 17R, 21P, 27P,34P, 35E 121 107 14E, 17R, 21P, 27P, 34H, 35E 387 108 14E, 17R, 21P,27P, 34R, 35E 232 109 14E, 17R, 21P, 27P, 34P, 35E 140 110 14E, 17R,21P, 27P, 34P, 35R 326 111 17R, 21P, 27P, 34H 580 113 17R, 21P, 27P, 34H382 114 14E, 17R, 21P, 27P, 34P, 37P 214 115 14H, 17R, 21P, 27P, 34P,37P 131 116 14H, 17R, 21P, 27P, 31P, 34P 82 117 14E, 17R, 21P, 27P, 34P,35R 163 118 14E, 17R, 21P, 27P, 34P, 35H 179 120 14S, 17R, 21P, 27P,34P, 35E 76 121 14E, 17R, 21P, 31P, 34P, 35E 69 122 14D, 17R, 21P, 27P,34P, 35E 172 123 14D, 17R, 21P, 27P, 34P, 35E 196 124 14E, 17R, 21P,27P, 34P, 35H 377 125 14E, 17R, 21P, 27P, 34P, 35E, 37P 533 127 14E,17R, 21P, 27P, 34P, 37F 152 129 14D, 17R, 21P, 27P, 34P, 35R 281 13014D, 17R, 21P, 27P, 34P, 35R 453 131 14d, 17R, 21P, 27P, 35R 365 13214D, 17R, 21P, 27P, 35R 266

Binding to Human Amylin Receptors and Human Calcitonin Receptors

The in vitro data regarding binding to human amylin receptors and humancalcitonin receptors and the corresponding selectivity values are shownin Table 5 (below).

Table 5 presents compounds that have a hAmylinR IC50 value of less than1200 pM and a ratio of hCT/hAmylin binding of less than or at least 10.The preferred compounds—which have a ratio of hCT/hAmylin binding of atleast 10—are presented in Table 5a (below). Details of the albuminbinding moiety, linker and acylation sites have been removed from theseTables. For full structural information please consult the entry with acorresponding compound number in Table 2. Further details regarding thecompounds, such as IUPAC nomenclature, may be found in Table 14.

TABLE 5 hAmylin- Ratio hCT/ R bind hCTR bind hAmylin Example no.Sequence modifications IC50 (pM) IC50 (pM) binding 1 14D, 17R, 21P, 26P,35D 1177 32473 27.6 2 14D, 17R, 21P, 27P, 35D 411 19538 47.5 3 14D, 17R,22P, 26P, 35D 1131 19505 17.3 4 14E, 17R, 21P, 25P, 28P, 29P, 37P 321688 2.1 5 14E, 17R, 21P, 26P, 37P 374 537 1.4 6 14E, 17R, 21P, 25P, 28P,29P 996 19950 20.0 7 14E, 17R, 21P, 26P 674 11140 16.5 8 14E, 17R, 21P,27P, 37P 72 38 0.5 9 14E, 17R, 21P, 27P 143 1142 8.0 10 14D, 17R, 21P,27P, 37P 82 99 1.2 11 14E, 17R, 21P, 27P, 35D, 37P 105 101 1.0 12 14E,17R, 21P, 27P, 37P 142 353 2.5 13 14E, 17R, 21P, 27P, 37P 264 305 1.2 1414E, 17R, 21P, 27P, 37P 196 432 2.2 15 14E, 17R, 21P, 27P 597 15510 26.016 14E, 17R, 21P, 27P, 35R 894 17070 19.1 17 14E, 17R, 21P, 27P, 34H 87810940 12.5 18 14E, 17R, 21P, 27P, 35H 554 5087 9.2 19 14E, 17R, 21P, 27P556 20390 36.7 20 14E, 17R, 21P, 27P, 37P 217 787 3.6 21 17R, 21P, 27P585 14240 24.4 22 14E, 17R, 21P, 27P, 35E 794 9729 12.3 23 17R, 21P,27P, 35E 871 21810 25.0 24 17R, 21P, 27P 1138 102400 90.0 25 17R, 21P,27P, 35E 768 43390 56.5 26 17R, 21P, 27P, 35E 532 25265 47.5 27 17R,21P, 27P, 35E 837 34545 41.3 28 17R, 21P, 27P, 31P, 35E 610 12522 20.529 17R, 21P, 27P, 34P, 35E 577 8006 13.9 30 14H, 17R, 21P, 27P, 35E 91921650 23.6 31 14E, 17R, 21P, 27P, 31P 204 3259 16.0 32 14E, 17R, 21P,27P, 34P 100 1088 10.9 33 14E, 17R, 21P, 28P, 35E 915 3606 3.9 34 17R,21P, 27P, 35K 1139 73390 64.4 35 17R, 21P, 27P, 35K 970 48750 50.3 3614E, 17R, 21P, 27P, 34K 403 6305 15.7 37 14E, 17R, 21P, 27P, 29P 9702184 2.3 38 17R, 21P, 27P, 35R 249 21170 84.9 39 17R, 21P, 27P, 34R 66519280 29.0 40 17R, 21P, 27P, 34H 549 17057 31.1 41 17R, 21P, 27P 42721310 49.9 42 17R, 21P, 27P 264 8105 30.7 43 17R, 21P, 27P 76 2636 34.744 −1K, 1R, 17R, 21P, 27P, 35H 275 4872 17.7 45 −1K, 1R, 17R, 21P, 27P,35H 552 14790 26.8 46 −1G, 1R, 17R, 21P, 27P 195 9530 48.9 47 −1G, 1R,17R, 21P, 27P, 35H 344 15460 44.9 48 17R, 21P, 27P 443 30870 69.7 4917R, 21P, 27P, 31P 1191 12861 10.8 50 17R, 21P, 27P, 34P 38 1380 36.0 5114E, 17R, 21P, 27P, 35R 828 31065 37.5 52 14D, 17R, 21P, 27P, 35R 69756874 81.6 53 17R, 21P, 27P, 28P, 31P 52 5383 103.5 54 17R, 21P, 27P,29P, 31P 30 4382 146.1 55 17R, 21P, 27P, 28P, 34P 42 2175 51.8 56 17R,21P, 27P, 29P, 34P 49 2088 42.6 57 17R, 21P, 27P, 31P, 35H 115 15300133.0 58 17R, 21P, 27P, 34P, 35H 88 9626 109.4 59 14D, 17R, 21K, 27P,35D 1193 5143 4.3 60 17R, 21P, 27P, 35H 695 31410 45.2 61 14H, 17R, 21P,27P, 31P 122 8111 66.7 62 14H, 17R, 21P, 27P, 31P 98 6174 63.0 63 14R,17R, 21P, 27P, 31P 825 129600 157.1 64 14R, 17R, 21P, 27P, 31P 444 55970126.1 65 14R, 17R, 21P, 27P, 34P 649 53461 82.4 66 14H, 17R, 21P, 27P,35H 396 18020 45.5 67 14H, 17R, 21P, 27P, 34P 90 4633 51.6 68 14H, 17R,21P, 27P, 34P 88 5664 64.4 69 14H, 17R, 21P, 27P 133 8680 65.3 70 14H,17R, 21P, 27P 169 10280 60.8 71 14G, 17R, 21P, 27P, 31P 48 1535 32.0 7214A, 17R, 21P, 27P, 31P 172 42410 246.6 73 14S, 17R, 21P, 27P, 31P 1045377 51.7 74 14K, 17R, 21P, 27P, 31P 791 79875 101.0 75 14T, 17R, 21P,27P, 31P 666 60870 91.4 76 17R, 21P, 27P, 34H 215 17207 80.0 77 17R,21P, 27P, 34H 428 50664 118.4 78 17R, 21P, 27P, 34R 602 36550 60.7 7917R, 21P, 27P, 34R 790 36390 46.1 80 14H, 17R, 21P, 27P, 34H 290 1976068.1 81 14H, 17R, 21P, 27P, 34H 271 23640 87.2 82 14R, 17R, 21P, 27P 63688760 139.6 83 14R, 17R, 21P, 27P 939 136700 145.6 84 14H, 17R, 21P,27P, 34R 743 88860 119.6 85 14H, 17R, 21P, 27P, 34R 876 80420 91.8 8617R, 21P, 27P, 34H 833 132723 159.3 87 14E, 17R, 21P, 27P, 34H 633 2252335.6 88 14E, 17R, 21P, 27P, 34R 750 34870 46.5 89 14E, 17R, 21P, 27P,35R 1160 32510 28.0 90 14H, 17R, 21P, 27P 61 2574 42.2 91 17R, 21P, 27P,34H 119 12000 100.8 92 14H, 17R, 21P, 27P 179 25960 145.0 93 14A, 17R,21P, 27P, 34H 176 17780 101.0 94 14A, 17R, 21P, 27P, 34P 148 6857 46.395 17R, 21P, 27P, 34R 967 61280 63.4 96 17R, 21P, 27P, 31P 166 1321079.6 97 17R, 21P, 27P, 34H 568 58920 103.7 98 17R, 21P, 27P, 34P 91 673974.1 99 −1G, 1R, 14H, 17R, 21P, 27P 348 34950 100.4 100 −1G, 1R, 14H,17R, 21P, 27P, 34H 1015 66275 65.3 101 −1G, 1R, 14A, 17R, 21P, 27P, 34H426 29175 68.6 102 −1G, 1R, 14H, 17R, 21P, 27P, 34P 217 7865 36.2 103−1G, 1R, 14A, 17R, 21P, 27P, 34P 114 3004 26.5 104 14E, 17R, 21P, 27P,34H, 35E 525 15245 29.1 105 14E, 17R, 21P, 27P, 34R, 35E 957 14099 14.7106 14E, 17R, 21P, 27P, 34P, 35E 121 2135 17.6 107 14E, 17R, 21P, 27P,34H, 35E 387 4283 11.1 108 14E, 17R, 21P, 27P, 34R, 35E 232 6623 28.5109 14E, 17R, 21P, 27P, 34P, 35E 140 1861 13.3 110 14E, 17R, 21P, 27P,34P, 35R 326 17455 53.6 111 17R, 21P, 27P, 34H 580 10750 18.5 112 17R,21P, 27P, 34H 1037 24320 23.5 113 17R, 21P, 27P, 34H 382 22690 59.4 11414E, 17R, 21P, 27P, 34P, 37P 214 117 0.5 115 14H, 17R, 21P, 27P, 34P,37P 131 157 1.2 116 14H, 17R, 21P, 27P, 31P, 34P 82 2036 24.8 117 14E,17R, 21P, 27P, 34P, 35R 163 6298 38.6 118 14E, 17R, 21P, 27P, 34P, 35H179 3801 21.2 119 17R, 21P, 27P, 31P, 34P, 35R 880 42770 48.6 120 14S,17R, 21P, 27P, 34P, 35E 76 3439 45.3 121 14E, 17R, 21P, 31P, 34P, 35E 691561 22.6 122 14D, 17R, 21P, 27P, 34P, 35E 172 8565 49.8 123 14D, 17R,21P, 27P, 34P, 35E 196 3273 16.7 124 14E, 17R, 21P, 27P, 34P, 35H 37710314 27.3 125 14E, 17R, 21P, 27P, 34P, 35E, 37P 533 226 0.4 126 14E,17R, 23P, 34P, 35E 1187 9294 7.8 127 14E, 17R, 21P, 27P, 34P, 37F 1522733 18.0 128 14E, 17R, 21P, 27P, 35H 992 26140 26.4 129 14D, 17R, 21P,27P, 34P, 35R 281 42470 151.1 130 14D, 17R, 21P, 27P, 34P, 35R 453126850 280.0 131 14d, 17R, 21P, 27P, 35R 365 111900 306.6 132 14D, 17R,21P, 27P, 35R 266 7504 28.2

TABLE 5a hAmylin- Ratio hCT/ R bind hCTR bind hAmylin Example no.Sequence modifications IC50 (pM) IC50 (pM) binding 1 14D, 17R, 21P, 26P,35D 1177 32473 27.6 2 14D, 17R, 21P, 27P, 35D 411 19538 47.5 3 14D, 17R,22P, 26P, 35D 1131 19505 17.3 6 14E, 17R, 21P, 25P, 28P, 29P 996 1995020.0 7 14E, 17R, 21P, 26P 674 11140 16.5 15 14E, 17R, 21P, 27P 597 1551026.0 16 14E, 17R, 21P, 27P, 35R 894 17070 19.1 17 14E, 17R, 21P, 27P,34H 878 10940 12.5 19 14E, 17R, 21P, 27P 556 20390 36.7 21 17R, 21P, 27P585 14240 24.4 22 14E, 17R, 21P, 27P, 35E 794 9729 12.3 23 17R, 21P,27P, 35E 871 21810 25.0 24 17R, 21P, 27P 1138 102400 90.0 25 17R, 21P,27P, 35E 768 43390 56.5 26 17R, 21P, 27P, 35E 532 25265 47.5 27 17R,21P, 27P, 35E 837 34545 41.3 28 17R, 21P, 27P, 31P, 35E 610 12522 20.529 17R, 21P, 27P, 34P, 35E 577 8006 13.9 30 14H, 17R, 21P, 27P, 35E 91921650 23.6 31 14E, 17R, 21P, 27P, 31P 204 3259 16.0 32 14E, 17R, 21P,27P, 34P 100 1088 10.9 34 17R, 21P, 27P, 35K 1139 73390 64.4 35 17R,21P, 27P, 35K 970 48750 50.3 36 14E, 17R, 21P, 27P, 34K 403 6305 15.7 3817R, 21P, 27P, 35R 249 21170 84.9 39 17R, 21P, 27P, 34R 665 19280 29.040 17R, 21P, 27P, 34H 549 17057 31.1 41 17R, 21P, 27P 427 21310 49.9 4217R, 21P, 27P 264 8105 30.7 43 17R, 21P, 27P 76 2636 34.7 44 −1K, 1R,17R, 21P, 27P, 35H 275 4872 17.7 45 −1K, 1R, 17R, 21P, 27P, 35H 55214790 26.8 46 −1G, 1R, 17R, 21P, 27P 195 9530 48.9 47 −1G, 1R, 17R, 21P,27P, 35H 344 15460 44.9 48 17R, 21P, 27P 443 30870 69.7 49 17R, 21P,27P, 31P 1191 12861 10.8 50 17R, 21P, 27P, 34P 38 1380 36.0 51 14E, 17R,21P, 27P, 35R 828 31065 37.5 52 14D, 17R, 21P, 27P, 35R 697 56874 81.653 17R, 21P, 27P, 28P, 31P 52 5383 103.5 54 17R, 21P, 27P, 29P, 31P 304382 146.1 55 17R, 21P, 27P, 28P, 34P 42 2175 51.8 56 17R, 21P, 27P,29P, 34P 49 2088 42.6 57 17R, 21P, 27P, 31P, 35H 115 15300 133.0 58 17R,21P, 27P, 34P, 35H 88 9626 109.4 60 17R, 21P, 27P, 35H 695 31410 45.2 6114H, 17R, 21P, 27P, 31P 122 8111 66.7 62 14H, 17R, 21P, 27P, 31P 98 617463.0 63 14R, 17R, 21P, 27P, 31P 825 129600 157.1 64 14R, 17R, 21P, 27P,31P 444 55970 126.1 65 14R, 17R, 21P, 27P, 34P 649 53461 82.4 66 14H,17R, 21P, 27P, 35H 396 18020 45.5 67 14H, 17R, 21P, 27P, 34P 90 463351.6 68 14H, 17R, 21P, 27P, 34P 88 5664 64.4 69 14H, 17R, 21P, 27P 1338680 65.3 70 14H, 17R, 21P, 27P 169 10280 60.8 71 14G, 17R, 21P, 27P,31P 48 1535 32.0 72 14A, 17R, 21P, 27P, 31P 172 42410 246.6 73 14S, 17R,21P, 27P, 31P 104 5377 51.7 74 14K, 17R, 21P, 27P, 31P 791 79875 101.075 14T, 17R, 21P, 27P, 31P 666 60870 91.4 76 17R, 21P, 27P, 34H 21517207 80.0 77 17R, 21P, 27P, 34H 428 50664 118.4 78 17R, 21P, 27P, 34R602 36550 60.7 79 17R, 21P, 27P, 34R 790 36390 46.1 80 14H, 17R, 21P,27P, 34H 290 19760 68.1 81 14H, 17R, 21P, 27P, 34H 271 23640 87.2 8214R, 17R, 21P, 27P 636 88760 139.6 83 14R, 17R, 21P, 27P 939 136700145.6 84 14H, 17R, 21P, 27P, 34R 743 88860 119.6 85 14H, 17R, 21P, 27P,34R 876 80420 91.8 86 17R, 21P, 27P, 34H 833 132723 159.3 87 14E, 17R,21P, 27P, 34H 633 22523 35.6 88 14E, 17R, 21P, 27P, 34R 750 34870 46.589 14E, 17R, 21P, 27P, 35R 1160 32510 28.0 90 14H, 17R, 21P, 27P 61 257442.2 91 17R, 21P, 27P, 34H 119 12000 100.8 92 14H, 17R, 21P, 27P 17925960 145.0 93 14A, 17R, 21P, 27P, 34H 176 17780 101.0 94 14A, 17R, 21P,27P, 34P 148 6857 46.3 95 17R, 21P, 27P, 34R 967 61280 63.4 96 17R, 21P,27P, 31P 166 13210 79.6 97 17R, 21P, 27P, 34H 568 58920 103.7 98 17R,21P, 27P, 34P 91 6739 74.1 99 −1G, 1R, 14H, 17R, 21P, 27P 348 34950100.4 100 −1G, 1R, 14H, 17R, 21P, 27P, 34H 1015 66275 65.3 101 −1G, 1R,14A, 17R, 21P, 27P, 34H 426 29175 68.6 102 −1G, 1R, 14H, 17R, 21P, 27P,34P 217 7865 36.2 103 −1G, 1R, 14A, 17R, 21P, 27P, 34P 114 3004 26.5 10414E, 17R, 21P, 27P, 34H, 35E 525 15245 29.1 105 14E, 17R, 21P, 27P, 34R,35E 957 14099 14.7 106 14E, 17R, 21P, 27P, 34P, 35E 121 2135 17.6 10714E, 17R, 21P, 27P, 34H, 35E 387 4283 11.1 108 14E, 17R, 21P, 27P, 34R,35E 232 6623 28.5 109 14E, 17R, 21P, 27P, 34P, 35E 140 1861 13.3 11014E, 17R, 21P, 27P, 34P, 35R 326 17455 53.6 111 17R, 21P, 27P, 34H 58010750 18.5 112 17R, 21P, 27P, 34H 1037 24320 23.5 113 17R, 21P, 27P, 34H382 22690 59.4 116 14H, 17R, 21P, 27P, 31P, 34P 82 2036 24.8 117 14E,17R, 21P, 27P, 34P, 35R 163 6298 38.6 118 14E, 17R, 21P, 27P, 34P, 35H179 3801 21.2 119 17R, 21P, 27P, 31P, 34P, 35R 880 42770 48.6 120 14S,17R, 21P, 27P, 34P, 35E 76 3439 45.3 121 14E, 17R, 21P, 31P, 34P, 35E 691561 22.6 122 14D, 17R, 21P, 27P, 34P, 35E 172 8565 49.8 123 14D, 17R,21P, 27P, 34P, 35E 196 3273 16.7 124 14E, 17R, 21P, 27P, 34P, 35H 37710314 27.3 127 14E, 17R, 21P, 27P, 34P, 37F 152 2733 18.0 128 14E, 17R,21P, 27P, 35H 992 26140 26.4 129 14D, 17R, 21P, 27P, 34P, 35R 281 42470151.1 130 14D, 17R, 21P, 27P, 34P, 35R 453 126850 280.0 131 14d, 17R,21P, 27P, 35R 365 111900 306.6 132 14D, 17R, 21P, 27P, 35R 266 7504 28.2

TABLE 5b hAmylin- Ratio hCT/ R bind hCTR bind hAmylin Example no.Sequence modifications IC50 (pM) IC50 (pM) binding 1 14D, 17R, 21P, 26P,35D 1177 32473 27.6 2 14D, 17R, 21P, 27P, 35D 411 19538 47.5 3 14D, 17R,22P, 26P, 35D 1131 19505 17.3 6 14E, 17R, 21P, 25P, 28P, 29P 996 1995020.0 7 14E, 17R, 21P, 26P 674 11140 16.5 15 14E, 17R, 21P, 27P 597 1551026.0 16 14E, 17R, 21P, 27P, 35R 894 17070 19.1 19 14E, 17R, 21P, 27P 55620390 36.7 21 17R, 21P, 27P 585 14240 24.4 23 17R, 21P, 27P, 35E 87121810 25.0 24 17R, 21P, 27P 1138 102400 90.0 25 17R, 21P, 27P, 35E 76843390 56.5 26 17R, 21P, 27P, 35E 532 25265 47.5 27 17R, 21P, 27P, 35E837 34545 41.3 28 17R, 21P, 27P, 31P, 35E 610 12522 20.5 30 14H, 17R,21P, 27P, 35E 919 21650 23.6 31 14E, 17R, 21P, 27P, 31P 204 3259 16.0 3417R, 21P, 27P, 35K 1139 73390 64.4 35 17R, 21P, 27P, 35K 970 48750 50.336 14E, 17R, 21P, 27P, 34K 403 6305 15.7 38 17R, 21P, 27P, 35R 249 2117084.9 39 17R, 21P, 27P, 34R 665 19280 29.0 40 17R, 21P, 27P, 34H 54917057 31.1 41 17R, 21P, 27P 427 21310 49.9 42 17R, 21P, 27P 264 810530.7 43 17R, 21P, 27P 76 2636 34.7 44 −1K, 1R, 17R, 21P, 27P, 35H 2754872 17.7 45 −1K, 1R, 17R, 21P, 27P, 35H 552 14790 26.8 46 −1G, 1R, 17R,21P, 27P 195 9530 48.9 47 −1G, 1R, 17R, 21P, 27P, 35H 344 15460 44.9 4817R, 21P, 27P 443 30870 69.7 50 17R, 21P, 27P, 34P 38 1380 36.0 51 14E,17R, 21P, 27P, 35R 828 31065 37.5 52 14D, 17R, 21P, 27P, 35R 697 5687481.6 53 17R, 21P, 27P, 28P, 31P 52 5383 103.5 54 17R, 21P, 27P, 29P, 31P30 4382 146.1 55 17R, 21P, 27P, 28P, 34P 42 2175 51.8 56 17R, 21P, 27P,29P, 34P 49 2088 42.6 57 17R, 21P, 27P, 31P, 35H 115 15300 133.0 58 17R,21P, 27P, 34P, 35H 88 9626 109.4 60 17R, 21P, 27P, 35H 695 31410 45.2 6114H, 17R, 21P, 27P, 31P 122 8111 66.7 62 14H, 17R, 21P, 27P, 31P 98 617463.0 63 14R, 17R, 21P, 27P, 31P 825 129600 157.1 64 14R, 17R, 21P, 27P,31P 444 55970 126.1 65 14R, 17R, 21P, 27P, 34P 649 53461 82.4 66 14H,17R, 21P, 27P, 35H 396 18020 45.5 67 14H, 17R, 21P, 27P, 34P 90 463351.6 68 14H, 17R, 21P, 27P, 34P 88 5664 64.4 69 14H, 17R, 21P, 27P 1338680 65.3 70 14H, 17R, 21P, 27P 169 10280 60.8 71 14G, 17R, 21P, 27P,31P 48 1535 32.0 72 14A, 17R, 21P, 27P, 31P 172 42410 246.6 73 14S, 17R,21P, 27P, 31P 104 5377 51.7 74 14K, 17R, 21P, 27P, 31P 791 79875 101.075 14T, 17R, 21P, 27P, 31P 666 60870 91.4 76 17R, 21P, 27P, 34H 21517207 80.0 77 17R, 21P, 27P, 34H 428 50664 118.4 78 17R, 21P, 27P, 34R602 36550 60.7 79 17R, 21P, 27P, 34R 790 36390 46.1 80 14H, 17R, 21P,27P, 34H 290 19760 68.1 81 14H, 17R, 21P, 27P, 34H 271 23640 87.2 8214R, 17R, 21P, 27P 636 88760 139.6 83 14R, 17R, 21P, 27P 939 136700145.6 84 14H, 17R, 21P, 27P, 34R 743 88860 119.6 85 14H, 17R, 21P, 27P,34R 876 80420 91.8 86 17R, 21P, 27P, 34H 833 132723 159.3 87 14E, 17R,21P, 27P, 34H 633 22523 35.6 88 14E, 17R, 21P, 27P, 34R 750 34870 46.589 14E, 17R, 21P, 27P, 35R 1160 32510 28.0 90 14H, 17R, 21P, 27P 61 257442.2 91 17R, 21P, 27P, 34H 119 12000 100.8 92 14H, 17R, 21P, 27P 17925960 145.0 93 14A, 17R, 21P, 27P, 34H 176 17780 101.0 94 14A, 17R, 21P,27P, 34P 148 6857 46.3 95 17R, 21P, 27P, 34R 967 61280 63.4 96 17R, 21P,27P, 31P 166 13210 79.6 97 17R, 21P, 27P, 34H 568 58920 103.7 98 17R,21P, 27P, 34P 91 6739 74.1 99 −1G, 1R, 14H, 17R, 21P, 27P 348 34950100.4 100 −1G, 1R, 14H, 17R, 21P, 27P, 34H 1015 66275 65.3 101 −1G, 1R,14A, 17R, 21P, 27P, 34H 426 29175 68.6 102 −1G, 1R, 14H, 17R, 21P, 27P,34P 217 7865 36.2 103 −1G, 1R, 14A, 17R, 21P, 27P, 34P 114 3004 26.5 10414E, 17R, 21P, 27P, 34H, 35E 525 15245 29.1 106 14E, 17R, 21P, 27P, 34P,35E 121 2135 17.6 108 14E, 17R, 21P, 27P, 34R, 35E 232 6623 28.5 10914E, 17R, 21P, 27P, 34P, 35E 140 1861 13.3 110 14E, 17R, 21P, 27P, 34P,35R 326 17455 53.6 111 17R, 21P, 27P, 34H 580 10750 18.5 112 17R, 21P,27P, 34H 1037 24320 23.5 113 17R, 21P, 27P, 34H 382 22690 59.4 116 14H,17R, 21P, 27P, 31P, 34P 82 2036 24.8 117 14E, 17R, 21P, 27P, 34P, 35R163 6298 38.6 118 14E, 17R, 21P, 27P, 34P, 35H 179 3801 21.2 119 17R,21P, 27P, 31P, 34P, 35R 880 42770 48.6 120 14S, 17R, 21P, 27P, 34P, 35E76 3439 45.3 121 14E, 17R, 21P, 31P, 34P, 35E 69 1561 22.6 122 14D, 17R,21P, 27P, 34P, 35E 172 8565 49.8 123 14D, 17R, 21P, 27P, 34P, 35E 1963273 16.7 124 14E, 17R, 21P, 27P, 34P, 35H 377 10314 27.3 127 14E, 17R,21P, 27P, 34P, 37F 152 2733 18.0 128 14E, 17R, 21P, 27P, 35H 992 2614026.4 129 14D, 17R, 21P, 27P, 34P, 35R 281 42470 151.1 130 14D, 17R, 21P,27P, 34P, 35R 453 126850 280.0 131 14d, 17R, 21P, 27P, 35R 365 111900306.6 132 14D, 17R, 21P, 27P, 35R 266 7504 28.2

TABLE 5c hAmylin- Ratio hCT/ R bind hCTR bind hAmylin Example no.Sequence modifications IC50 (pM) IC50 (pM) binding 1 14D, 17R, 21P, 26P,35D 1177 32473 27.6 2 14D, 17R, 21P, 27P, 35D 411 19538 47.5 6 14E, 17R,21P, 25P, 28P, 29P 996 19950 20.0 15 14E, 17R, 21P, 27P 597 15510 26.019 14E, 17R, 21P, 27P 556 20390 36.7 21 17R, 21P, 27P 585 14240 24.4 2317R, 21P, 27P, 35E 871 21810 25.0 24 17R, 21P, 27P 1138 102400 90.0 2517R, 21P, 27P, 35E 768 43390 56.5 26 17R, 21P, 27P, 35E 532 25265 47.527 17R, 21P, 27P, 35E 837 34545 41.3 28 17R, 21P, 27P, 31P, 35E 61012522 20.5 30 14H, 17R, 21P, 27P, 35E 919 21650 23.6 34 17R, 21P, 27P,35K 1139 73390 64.4 35 17R, 21P, 27P, 35K 970 48750 50.3 38 17R, 21P,27P, 35R 249 21170 84.9 39 17R, 21P, 27P, 34R 665 19280 29.0 40 17R,21P, 27P, 34H 549 17057 31.1 41 17R, 21P, 27P 427 21310 49.9 42 17R,21P, 27P 264 8105 30.7 43 17R, 21P, 27P 76 2636 34.7 45 −1K, 1R, 17R,21P, 27P, 35H 552 14790 26.8 46 −1G, 1R, 17R, 21P, 27P 195 9530 48.9 47−1G, 1R, 17R, 21P, 27P, 35H 344 15460 44.9 48 17R, 21P, 27P 443 3087069.7 50 17R, 21P, 27P, 34P 38 1380 36.0 51 14E, 17R, 21P, 27P, 35R 82831065 37.5 52 14D, 17R, 21P, 27P, 35R 697 56874 81.6 53 17R, 21P, 27P,28P, 31P 52 5383 103.5 54 17R, 21P, 27P, 29P, 31P 30 4382 146.1 55 17R,21P, 27P, 28P, 34P 42 2175 51.8 56 17R, 21P, 27P, 29P, 34P 49 2088 42.657 17R, 21P, 27P, 31P, 35H 115 15300 133.0 58 17R, 21P, 27P, 34P, 35H 889626 109.4 60 17R, 21P, 27P, 35H 695 31410 45.2 61 14H, 17R, 21P, 27P,31P 122 8111 66.7 62 14H, 17R, 21P, 27P, 31P 98 6174 63.0 63 14R, 17R,21P, 27P, 31P 825 129600 157.1 64 14R, 17R, 21P, 27P, 31P 444 55970126.1 65 14R, 17R, 21P, 27P, 34P 649 53461 82.4 66 14H, 17R, 21P, 27P,35H 396 18020 45.5 67 14H, 17R, 21P, 27P, 34P 90 4633 51.6 68 14H, 17R,21P, 27P, 34P 88 5664 64.4 69 14H, 17R, 21P, 27P 133 8680 65.3 70 14H,17R, 21P, 27P 169 10280 60.8 71 14G, 17R, 21P, 27P, 31P 48 1535 32.0 7214A, 17R, 21P, 27P, 31P 172 42410 246.6 73 14S, 17R, 21P, 27P, 31P 1045377 51.7 74 14K, 17R, 21P, 27P, 31P 791 79875 101.0 75 14T, 17R, 21P,27P, 31P 666 60870 91.4 76 17R, 21P, 27P, 34H 215 17207 80.0 77 17R,21P, 27P, 34H 428 50664 118.4 78 17R, 21P, 27P, 34R 602 36550 60.7 7917R, 21P, 27P, 34R 790 36390 46.1 80 14H, 17R, 21P, 27P, 34H 290 1976068.1 81 14H, 17R, 21P, 27P, 34H 271 23640 87.2 82 14R, 17R, 21P, 27P 63688760 139.6 83 14R, 17R, 21P, 27P 939 136700 145.6 84 14H, 17R, 21P,27P, 34R 743 88860 119.6 85 14H, 17R, 21P, 27P, 34R 876 80420 91.8 8617R, 21P, 27P, 34H 833 132723 159.3 87 14E, 17R, 21P, 27P, 34H 633 2252335.6 88 14E, 17R, 21P, 27P, 34R 750 34870 46.5 89 14E, 17R, 21P, 27P,35R 1160 32510 28.0 90 14H, 17R, 21P, 27P 61 2574 42.2 91 17R, 21P, 27P,34H 119 12000 100.8 92 14H, 17R, 21P, 27P 179 25960 145.0 93 14A, 17R,21P, 27P, 34H 176 17780 101.0 94 14A, 17R, 21P, 27P, 34P 148 6857 46.395 17R, 21P, 27P, 34R 967 61280 63.4 96 17R, 21P, 27P, 31P 166 1321079.6 97 17R, 21P, 27P, 34H 568 58920 103.7 98 17R, 21P, 27P, 34P 91 673974.1 99 −1G, 1R, 14H, 17R, 21P, 27P 348 34950 100.4 100 −1G, 1R, 14H,17R, 21P, 27P, 34H 1015 66275 65.3 101 −1G, 1R, 14A, 17R, 21P, 27P, 34H426 29175 68.6 102 −1G, 1R, 14H, 17R, 21P, 27P, 34P 217 7865 36.2 103−1G, 1R, 14A, 17R, 21P, 27P, 34P 114 3004 26.5 104 14E, 17R, 21P, 27P,34H, 35E 525 15245 29.1 108 14E, 17R, 21P, 27P, 34R, 35E 232 6623 28.5109 14E, 17R, 21P, 27P, 34P, 35E 140 1861 13.3 110 14E, 17R, 21P, 27P,34P, 35R 326 17455 53.6 111 17R, 21P, 27P, 34H 580 10750 18.5 112 17R,21P, 27P, 34H 1037 24320 23.5 113 17R, 21P, 27P, 34H 382 22690 59.4 11614H, 17R, 21P, 27P, 31P, 34P 82 2036 24.8 117 14E, 17R, 21P, 27P, 34P,35R 163 6298 38.6 118 14E, 17R, 21P, 27P, 34P, 35H 179 3801 21.2 11917R, 21P, 27P, 31P, 34P, 35R 880 42770 48.6 120 14S, 17R, 21P, 27P, 34P,35E 76 3439 45.3 121 14E, 17R, 21P, 31P, 34P, 35E 69 1561 22.6 122 14D,17R, 21P, 27P, 34P, 35E 172 8565 49.8 124 14E, 17R, 21P, 27P, 34P, 35H377 10314 27.3 128 14E, 17R, 21P, 27P, 35H 992 26140 26.4 129 14D, 17R,21P, 27P, 34P, 35R 281 42470 151.1 130 14D, 17R, 21P, 27P, 34P, 35R 453126850 280.0 131 14d, 17R, 21P, 27P, 35R 365 111900 306.6 132 14D, 17R,21P, 27P, 35R 266 7504 28.2

Human Amylin Receptor Potency and Human Calcitonin Receptor Potency

The in vitro data regarding human amylin receptor potency and humancalcitonin receptor potency (measured as described in assay (II)) andthe corresponding selectivity values are shown in Table 6. For ease ofreference, the human binding data are also included.

Table 6 discloses compounds that have a hAmylinR IC₅₀ value of less than1200 pM and indicates values for human functional selectivity of atleast 5 or less than 5. Preferred compounds have a hAmylinR IC50 valueof less than 1200 pM and a human functional selectivity of at least 5.For ease of reference, these preferred compounds are presented in Table6a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 6. In oneembodiment the amylin polypeptide according to the present invention isselected from the compounds presented in table 6a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds presented in table 6b. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6c. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6d. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6e. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6f. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6g. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6h. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6i. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6j. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6k. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6l. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6m. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6n. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6o.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6 and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6 and table 4a. In one embodiment the amylin polypeptide accordingto the present invention is selected from the compounds which are incommon between the presented compounds of in table 6 and table 4b. Inone embodiment the amylin polypeptide according to the present inventionis selected from the compounds which are in common between the presentedcompounds of in table 6 and table 4a. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds which are in common between the presented compounds of intable 6 and table 4c. In one embodiment the amylin polypeptide accordingto the present invention is selected from the compounds which are incommon between the presented compounds of in table 6 and table 5. In oneembodiment the amylin polypeptide according to the present invention isselected from the compounds which are in common between the presentedcompounds of in table 6 and table 5a. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds which are in common between the presented compounds of intable 6 and table 5b. In one embodiment the amylin polypeptide accordingto the present invention is selected from the compounds which are incommon between the presented compounds of in table 6 and table 5c. Inone embodiment the amylin polypeptide according to the present inventionis selected from the compounds which are in common between the presentedcompounds of in table 6 and table 8. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds which are in common between the presented compounds of intable 6 and table 8a. In one embodiment the amylin polypeptide accordingto the present invention is selected from the compounds which are incommon between the presented compounds of in table 6 and table 9. In oneembodiment the amylin polypeptide according to the present invention isselected from the compounds which are in common between the presentedcompounds of in table 6 and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6a and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6a and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6a and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6a and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6a and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6a and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6a and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6a and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6a and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6a and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6a and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6a and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6a and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6b and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6b and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6 band table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6b and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6b and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6b and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6b and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6b and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6b and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6b and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6b and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6b and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6b and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6c and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6c and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6c and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6c and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6c and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6c and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6c and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6c and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6c and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6b and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6b and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6b and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6b and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6d and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6d and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6d and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6d and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6d and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6d and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6d and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6d and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6d and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6c and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6c and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6c and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6c and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6e and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6e and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6e and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6e and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6e and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6e and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6e and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6e and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6e and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6e and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6e and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6e and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6e and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6f and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6f and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6f and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6f and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6f and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6f and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6f and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6f and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6f and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6f and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6f and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6f and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6f and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6g and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6g and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6g and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6g and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6g and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6g and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6g and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6g and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6g and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6g and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6g and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6g and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6g and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6h and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6h and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6h and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6h and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6h and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6h and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6h and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6h and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6h and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6h and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6h and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6h and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6h and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6i and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6i and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6i and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6i and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6i and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6i and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6i and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6i and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6i and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6i and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6i and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6i and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6i and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6j and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6j and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6j and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6j and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6j and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6j and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6j and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6j and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6j and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6j and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6j and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6j and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6j and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6k and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6k and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6k and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6k and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6k and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6k and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6k and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6k and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6k and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6k and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6k and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6k and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6k and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6l and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6l and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6l and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6l and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6l and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6l and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6l and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6l and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6l and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6l and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6l and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6l and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6l and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6m and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6m and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6m and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6m and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6m and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6m and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6m and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6m and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6m and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6m and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6m and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6m and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6m and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6n and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6n and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6n and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6n and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6n and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6n and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6n and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6n and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6n and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6n and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6n and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6n and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6n and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6o and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6o and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6o and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6o and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6o and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6o and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6o and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6o and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6o and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6o and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 6o and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 6o and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 6o and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 6, exceptthe compounds presented in table 6d. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6, except the compounds presented in table6e. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 6, exceptthe compounds presented in table 6f. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6, except the compounds presented in table6h. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 6, exceptthe compounds presented in table 6l. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6, except the compounds presented in table6o.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 6a, exceptthe compounds presented in table 6d. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6a, except the compounds presented in table6e. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 6a, exceptthe compounds presented in table 6f. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6a, except the compounds presented in table6h. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 6a, exceptthe compounds presented in table 6l. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 6a, except the compounds presented in table6o.

In one embodiment the amylin compound according to this invention Iselected form the group consisting of compound (example) no: 52, 86, 89,118, 109 or 106.

In one embodiment the amylin compound according to this invention Iselected form the group consisting of compound (example) no: 52. In oneembodiment the amylin compound according to this invention I selectedform the group consisting of compound (example) no: 86. In oneembodiment the amylin compound according to this invention I selectedform the group consisting of compound (example) no: 89. In oneembodiment the amylin compound according to this invention I selectedform the group consisting of compound (example) no: 118. In oneembodiment the amylin compound according to this invention I selectedform the group consisting of compound (example) no: 109. In oneembodiment the amylin compound according to this invention I selectedform the group consisting of compound (example) no: 106.

Details of the albumin binding moiety, linker and acylation sites havebeen removed from these Tables. For full structural information pleaseconsult the entry with a corresponding compound number in Table 2.Further details regarding the compounds, such as IUPAC nomenclature maybe found in Table 14.

TABLE 6 hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 1 14D, 17R, 21P, 26P, 35D 1177 224 2697 12.0 2 14D, 17R, 21P,27P, 35D 411 182 2998 16.4 3 14D, 17R, 22P, 26P, 35D 1131 205 1380 6.7 414E, 17R, 21P, 25P, 28P, 29P, 321 60 70 1.2 37P 5 14E, 17R, 21P, 26P,37P 374 162 160 1.0 6 14E, 17R, 21P, 25P, 28P, 29P 996 128 729 5.7 714E, 17R, 21P, 26P 674 255 1156 4.5 8 14E, 17R, 21P, 27P, 37P 72 82 871.1 9 14E, 17R, 21P, 27P 143 175 1288 7.4 10 14D, 17R, 21P, 27P, 37P 8272 70 1.0 11 14E, 17R, 21P, 27P, 35D, 37P 105 120 112 0.9 12 14E, 17R,21P, 27P, 37P 142 101 185 1.8 13 14E, 17R, 21P, 27P, 37P 264 213 470 2.214 14E, 17R, 21P, 27P, 37P 196 146 238 1.6 15 14E, 17R, 21P, 27P 597 3863432 8.9 16 14E, 17R, 21P, 27P, 35R 894 363 2215 6.1 17 14E, 17R, 21P,27P, 34H 878 268 2351 8.8 18 14E, 17R, 21P, 27P, 35H 554 154 742 4.8 1914E, 17R, 21P, 27P 556 307 5321 17.4 20 14E, 17R, 21P, 27P, 37P 217 80285 3.6 21 17R, 21P, 27P 585 148 611 4.1 22 14E, 17R, 21P, 27P, 35E 794270 1026 3.8 23 17R, 21P, 27P, 35E 871 340 3025 8.9 24 17R, 21P, 27P1138 433 10000 23.1 25 17R, 21P, 27P, 35E 768 217 10000 46.2 26 17R,21P, 27P, 35E 532 212 6338 29.9 27 17R, 21P, 27P, 35E 837 133 3001 22.628 17R, 21P, 27P, 31P, 35E 610 220 2033 9.2 29 17R, 21P, 27P, 34P, 35E577 99 857 8.7 30 14H, 17R, 21P, 27P, 35E 919 134 1677 12.6 31 14E, 17R,21P, 27P, 31P 204 112 717 6.4 32 14E, 17R, 21P, 27P, 34P 100 50 327 6.633 14E, 17R, 21P, 28P, 35E 915 243 528 2.2 34 17R, 21P, 27P, 35K 1139313 2615 8.4 35 17R, 21P, 27P, 35K 970 364 5459 15.0 36 14E, 17R, 21P,27P, 34K 403 189 1280 6.8 37 14E, 17R, 21P, 27P, 29P 970 92 372 4.0 3817R, 21P, 27P, 35R 249 352 18260 51.9 39 17R, 21P, 27P, 34R 665 217 252211.6 40 17R, 21P, 27P, 34H 549 164 2680 16.4 41 17R, 21P, 27P 427 2604346 16.7 42 17R, 21P, 27P 264 146 1975 13.5 43 17R, 21P, 27P 76 141 9206.5 44 −1K, 1R, 17R, 21P, 27P, 35H 275 198 4751 24.0 45 −1K, 1R, 17R,21P, 27P, 35H 552 594 10100 17.0 46 −1G, 1R, 17R, 21P, 27P 195 88 89910.2 47 −1G, 1R, 17R, 21P, 27P, 35H 344 222 1322 6.0 48 17R, 21P, 27P443 116 1968 17.0 49 17R, 21P, 27P, 31P 1191 106 2390 22.5 50 17R, 21P,27P, 34P 38 38 662 17.4 51 14E, 17R, 21P, 27P, 35R 828 372 5216 14.0 5214D, 17R, 21P, 27P, 35R 697 340 14074 41.4 53 17R, 21P, 27P, 28P, 31P 5264 625 9.8 54 17R, 21P, 27P, 29P, 31P 30 103 987 9.6 55 17R, 21P, 27P,28P, 34P 42 68 731 10.8 56 17R, 21P, 27P, 29P, 34P 49 102 506 5.0 5717R, 21P, 27P, 31P, 35H 115 89 3119 35.0 58 17R, 21P, 27P, 34P, 35H 8847 1028 21.9 59 14D, 17R, 21K, 27P, 35D 1193 389 1953 5.0 60 17R, 21P,27P, 35H 695 351 5355 15.3 61 14H, 17R, 21P, 27P, 31P 122 51 554 10.9 6214H, 17R, 21P, 27P, 31P 98 44 539 12.3 63 14R, 17R, 21P, 27P, 31P 825 375131 138.7 64 14R, 17R, 21P, 27P, 31P 444 378 22940 60.7 65 14R, 17R,21P, 27P, 34P 649 242 9331 38.6 66 14H, 17R, 21P, 27P, 35H 396 27 54220.1 67 14H, 17R, 21P, 27P, 34P 90 69 354 5.2 68 14H, 17R, 21P, 27P, 34P88 54 932 17.4 69 14H, 17R, 21P, 27P 133 94 1248 13.3 70 14H, 17R, 21P,27P 169 40 715 17.9 71 14G, 17R, 21P, 27P, 31P 48 56 527 9.4 72 14A,17R, 21P, 27P, 31P 172 106 4758 44.9 73 14S, 17R, 21P, 27P, 31P 104 85961 11.3 74 14K, 17R, 21P, 27P, 31P 791 666 37520 56.3 75 14T, 17R, 21P,27P, 31P 666 296 9069 30.6 76 17R, 21P, 27P, 34H 215 297 7370 24.8 7717R, 21P, 27P, 34H 428 145 5398 37.3 78 17R, 21P, 27P, 34R 602 316 816525.8 79 17R, 21P, 27P, 34R 790 161 3938 24.5 80 14H, 17R, 21P, 27P, 34H290 139 2141 15.4 81 14H, 17R, 21P, 27P, 34H 271 130 1727 13.3 82 14R,17R, 21P, 27P 636 215 12730 59.2 83 14R, 17R, 21P, 27P 939 405 1684041.6 84 14H, 17R, 21P, 27P, 34R 743 169 5486 32.5 85 14H, 17R, 21P, 27P,34R 876 146 3882 26.6 86 17R, 21P, 27P, 34H 833 298 19157 64.4 87 14E,17R, 21P, 27P, 34H 633 285 1095 3.8 88 14E, 17R, 21P, 27P, 34R 750 7736555 8.5 89 14E, 17R, 21P, 27P, 35R 1160 404 11221 27.8 90 14H, 17R,21P, 27P 61 33 236 7.2 91 17R, 21P, 27P, 34H 119 40 1477 36.9 92 14H,17R, 21P, 27P 179 85 2378 28.0 93 14A, 17R, 21P, 27P, 34H 176 118 11459.7 94 14A, 17R, 21P, 27P, 34P 148 70 316 4.5 95 17R, 21P, 27P, 34R 967651 21500 33.0 96 17R, 21P, 27P, 31P 166 181 3801 21.0 97 17R, 21P, 27P,34H 568 356 11750 33.0 98 17R, 21P, 27P, 34P 91 84 1634 19.5 99 −1G, 1R,14H, 17R, 21P, 27P 348 82 818 10.0 100 −1G, 1R, 14H, 17R, 21P, 27P, 1015253 1726 6.8 34H 101 −1G, 1R, 14A, 17R, 21P, 27P, 426 109 537 4.9 34H102 −1G, 1R, 14H, 17R, 21P, 27P, 217 62 179 2.9 34P 103 −1G, 1R, 14A,17R, 21P, 27P, 114 70 148 2.1 34P 104 14E, 17R, 21P, 27P, 34H, 35E 525445 7053 15.8 105 14E, 17R, 21P, 27P, 34R, 35E 957 703 7426 10.6 10614E, 17R, 21P, 27P, 34P, 35E 121 225 2362 10.5 107 14E, 17R, 21P, 27P,34H, 35E 387 405 2541 6.3 108 14E, 17R, 21P, 27P, 34R, 35E 232 421 27456.5 109 14E, 17R, 21P, 27P, 34P, 35E 140 161 841 5.2 110 14E, 17R, 21P,27P, 34P, 35R 326 278 8158 29.3 111 17R, 21P, 27P, 34H 580 34 2214 65.1112 17R, 21P, 27P, 34H 1037 28 1087 38.8 113 17R, 21P, 27P, 34H 382 965846 60.9 114 14E, 17R, 21P, 27P, 34P, 37P 214 105 90 0.9 115 14H, 17R,21P, 27P, 34P, 37P 131 52 40 0.8 116 14H, 17R, 21P, 27P, 31P, 34P 82 71345 4.9 117 14E, 17R, 21P, 27P, 34P, 35R 163 376 6380 17.0 118 14E, 17R,21P, 27P, 34P, 35H 179 101 1451 14.4 119 17R, 21P, 27P, 31P, 34P, 35R880 333 8660 26.0 120 14S, 17R, 21P, 27P, 34P, 35E 76 109 887 8.1 12114E, 17R, 21P, 31P, 34P, 35E 69 222 1280 5.8 122 14D, 17R, 21P, 27P,34P, 35E 172 159 843 5.3 123 14D, 17R, 21P, 27P, 34P, 35E 196 288 11153.9 124 14E, 17R, 21P, 27P, 34P, 35H 377 172 2833 16.4 125 14E, 17R,21P, 27P, 34P, 35E, 533 132 102 0.8 37P 126 14E, 17R, 23P, 34P, 35E 11875168 89580 17.3 127 14E, 17R, 21P, 27P, 34P, 37F 152 216 2140 9.9 12814E, 17R, 21P, 27P, 35H 992 425 5575 13.1 129 14D, 17R, 21P, 27P, 34P,35R 281 146 3640 24.9 130 14D, 17R, 21P, 27P, 34P, 35R 453 162 7280 44.9131 14d, 17R, 21P, 27P, 35R 365 383 100000 261.1 132 14D, 17R, 21P, 27P,35R 266 11 318 28.9

TABLE 6a hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 1 14D, 17R, 21P, 26P, 35D 1177 224 2697 12.0 2 14D, 17R, 21P,27P, 35D 411 182 2998 16.4 3 14D, 17R, 22P, 26P, 35D 1131 205 1380 6.7 614E, 17R, 21P, 25P, 28P, 29P 996 128 729 5.7 9 14E, 17R, 21P, 27P 143175 1288 7.4 15 14E, 17R, 21P, 27P 597 386 3432 8.9 16 14E, 17R, 21P,27P, 35R 894 363 2215 6.1 17 14E, 17R, 21P, 27P, 34H 878 268 2351 8.8 1914E, 17R, 21P, 27P 556 307 5321 17.4 23 17R, 21P, 27P, 35E 871 340 30258.9 24 17R, 21P, 27P 1138 433 10000 23.1 25 17R, 21P, 27P, 35E 768 21710000 46.2 26 17R, 21P, 27P, 35E 532 212 6338 29.9 27 17R, 21P, 27P, 35E837 133 3001 22.6 28 17R, 21P, 27P, 31P, 35E 610 220 2033 9.2 29 17R,21P, 27P, 34P, 35E 577 99 857 8.7 30 14H, 17R, 21P, 27P, 35E 919 1341677 12.6 31 14E, 17R, 21P, 27P, 31P 204 112 717 6.4 32 14E, 17R, 21P,27P, 34P 100 50 327 6.6 34 17R, 21P, 27P, 35K 1139 313 2615 8.4 35 17R,21P, 27P, 35K 970 364 5459 15.0 36 14E, 17R, 21P, 27P, 34K 403 189 12806.8 38 17R, 21P, 27P, 35R 249 352 18260 51.9 39 17R, 21P, 27P, 34R 665217 2522 11.6 40 17R, 21P, 27P, 34H 549 164 2680 16.4 41 17R, 21P, 27P427 260 4346 16.7 42 17R, 21P, 27P 264 146 1975 13.5 43 17R, 21P, 27P 76141 920 6.5 44 −1K, 1R, 17R, 21P, 27P, 35H 275 198 4751 24.0 45 −1K, 1R,17R, 21P, 27P, 35H 552 594 10100 17.0 46 −1G, 1R, 17R, 21P, 27P 195 88899 10.2 47 −1G, 1R, 17R, 21P, 27P, 35H 344 222 1322 6.0 48 17R, 21P,27P 443 116 1968 17.0 49 17R, 21P, 27P, 31P 1191 106 2390 22.5 50 17R,21P, 27P, 34P 38 38 662 17.4 51 14E, 17R, 21P, 27P, 35R 828 372 521614.0 52 14D, 17R, 21P, 27P, 35R 697 340 14074 41.4 53 17R, 21P, 27P,28P, 31P 52 64 625 9.8 54 17R, 21P, 27P, 29P, 31P 30 103 987 9.6 55 17R,21P, 27P, 28P, 34P 42 68 731 10.8 56 17R, 21P, 27P, 29P, 34P 49 102 5065.0 57 17R, 21P, 27P, 31P, 35H 115 89 3119 35.0 58 17R, 21P, 27P, 34P,35H 88 47 1028 21.9 59 14D, 17R, 21K, 27P, 35D 1193 389 1953 5.0 60 17R,21P, 27P, 35H 695 351 5355 15.3 61 14H, 17R, 21P, 27P, 31P 122 51 55410.9 62 14H, 17R, 21P, 27P, 31P 98 44 539 12.3 63 14R, 17R, 21P, 27P,31P 825 37 5131 138.7 64 14R, 17R, 21P, 27P, 31P 444 378 22940 60.7 6514R, 17R, 21P, 27P, 34P 649 242 9331 38.6 66 14H, 17R, 21P, 27P, 35H 39627 542 20.1 67 14H, 17R, 21P, 27P, 34P 90 69 354 5.2 68 14H, 17R, 21P,27P, 34P 88 54 932 17.4 69 14H, 17R, 21P, 27P 133 94 1248 13.3 70 14H,17R, 21P, 27P 169 40 715 17.9 71 14G, 17R, 21P, 27P, 31P 48 56 527 9.472 14A, 17R, 21P, 27P, 31P 172 106 4758 44.9 73 14S, 17R, 21P, 27P, 31P104 85 961 11.3 74 14K, 17R, 21P, 27P, 31P 791 666 37520 56.3 75 14T,17R, 21P, 27P, 31P 666 296 9069 30.6 76 17R, 21P, 27P, 34H 215 297 737024.8 77 17R, 21P, 27P, 34H 428 145 5398 37.3 78 17R, 21P, 27P, 34R 602316 8165 25.8 79 17R, 21P, 27P, 34R 790 161 3938 24.5 80 14H, 17R, 21P,27P, 34H 290 139 2141 15.4 81 14H, 17R, 21P, 27P, 34H 271 130 1727 13.382 14R, 17R, 21P, 27P 636 215 12730 59.2 83 14R, 17R, 21P, 27P 939 40516840 41.6 84 14H, 17R, 21P, 27P, 34R 743 169 5486 32.5 85 14H, 17R,21P, 27P, 34R 876 146 3882 26.6 86 17R, 21P, 27P, 34H 833 298 19157 64.488 14E, 17R, 21P, 27P, 34R 750 773 6555 8.5 89 14E, 17R, 21P, 27P, 35R1160 404 11221 27.8 90 14H, 17R, 21P, 27P 61 33 236 7.2 91 17R, 21P,27P, 34H 119 40 1477 36.9 92 14H, 17R, 21P, 27P 179 85 2378 28.0 93 14A,17R, 21P, 27P, 34H 176 118 1145 9.7 95 17R, 21P, 27P, 34R 967 651 2150033.0 96 17R, 21P, 27P, 31P 166 181 3801 21.0 97 17R, 21P, 27P, 34H 568356 11750 33.0 98 17R, 21P, 27P, 34P 91 84 1634 19.5 99 −1G, 1R, 14H,17R, 21P, 27P 348 82 818 10.0 100 −1G, 1R, 14H, 17R, 21P, 27P, 1015 2531726 6.8 34H 104 14E, 17R, 21P, 27P, 34H, 35E 525 445 7053 15.8 105 14E,17R, 21P, 27P, 34R, 35E 957 703 7426 10.6 106 14E, 17R, 21P, 27P, 34P,35E 121 225 2362 10.5 107 14E, 17R, 21P, 27P, 34H, 35E 387 405 2541 6.3108 14E, 17R, 21P, 27P, 34R, 35E 232 421 2745 6.5 109 14E, 17R, 21P,27P, 34P, 35E 140 161 841 5.2 110 14E, 17R, 21P, 27P, 34P, 35R 326 2788158 29.3 111 17R, 21P, 27P, 34H 580 34 2214 65.1 112 17R, 21P, 27P, 34H1037 28 1087 38.8 113 17R, 21P, 27P, 34H 382 96 5846 60.9 117 14E, 17R,21P, 27P, 34P, 35R 163 376 6380 17.0 118 14E, 17R, 21P, 27P, 34P, 35H179 101 1451 14.4 119 17R, 21P, 27P, 31P, 34P, 35R 880 333 8660 26.0 12014S, 17R, 21P, 27P, 34P, 35E 76 109 887 8.1 121 14E, 17R, 21P, 31P, 34P,35E 69 222 1280 5.8 122 14D, 17R, 21P, 27P, 34P, 35E 172 159 843 5.3 12414E, 17R, 21P, 27P, 34P, 35H 377 172 2833 16.4 126 14E, 17R, 23P, 34P,35E 1187 5168 89580 17.3 127 14E, 17R, 21P, 27P, 34P, 37F 152 216 21409.9 128 14E, 17R, 21P, 27P, 35H 992 425 5575 13.1 129 14D, 17R, 21P,27P, 34P, 35R 281 146 3640 24.9 130 14D, 17R, 21P, 27P, 34P, 35R 453 1627280 44.9 131 14d, 17R, 21P, 27P, 35R 365 383 100000 261.1 132 14D, 17R,21P, 27P, 35R 266 11 318 28.9

TABLE 6b hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 1 14D, 17R, 21P, 26P, 35D 1177 224 2697 12.0 2 14D, 17R, 21P,27P, 35D 411 182 2998 16.4 19 14E, 17R, 21P, 27P 556 307 5321 17.4 2417R, 21P, 27P 1138 433 10000 23.1 25 17R, 21P, 27P, 35E 768 217 1000046.2 26 17R, 21P, 27P, 35E 532 212 6338 29.9 27 17R, 21P, 27P, 35E 837133 3001 22.6 30 14H, 17R, 21P, 27P, 35E 919 134 1677 12.6 35 17R, 21P,27P, 35K 970 364 5459 15.0 38 17R, 21P, 27P, 35R 249 352 18260 51.9 3917R, 21P, 27P, 34R 665 217 2522 11.6 40 17R, 21P, 27P, 34H 549 164 268016.4 41 17R, 21P, 27P 427 260 4346 16.7 42 17R, 21P, 27P 264 146 197513.5 44 −1K, 1R, 17R, 21P, 27P, 35H 275 198 4751 24.0 45 −1K, 1R, 17R,21P, 27P, 35H 552 594 10100 17.0 46 −1G, 1R, 17R, 21P, 27P 195 88 89910.2 48 17R, 21P, 27P 443 116 1968 17.0 49 17R, 21P, 27P, 31P 1191 1062390 22.5 50 17R, 21P, 27P, 34P 38 38 662 17.4 51 14E, 17R, 21P, 27P,35R 828 372 5216 14.0 52 14D, 17R, 21P, 27P, 35R 697 340 14074 41.4 5517R, 21P, 27P, 28P, 34P 42 68 731 10.8 57 17R, 21P, 27P, 31P, 35H 115 893119 35.0 58 17R, 21P, 27P, 34P, 35H 88 47 1028 21.9 60 17R, 21P, 27P,35H 695 351 5355 15.3 61 14H, 17R, 21P, 27P, 31P 122 51 554 10.9 62 14H,17R, 21P, 27P, 31P 98 44 539 12.3 63 14R, 17R, 21P, 27P, 31P 825 37 5131138.7 64 14R, 17R, 21P, 27P, 31P 444 378 22940 60.7 65 14R, 17R, 21P,27P, 34P 649 242 9331 38.6 66 14H, 17R, 21P, 27P, 35H 396 27 542 20.1 6814H, 17R, 21P, 27P, 34P 88 54 932 17.4 69 14H, 17R, 21P, 27P 133 94 124813.3 70 14H, 17R, 21P, 27P 169 40 715 17.9 72 14A, 17R, 21P, 27P, 31P172 106 4758 44.9 73 14S, 17R, 21P, 27P, 31P 104 85 961 11.3 74 14K,17R, 21P, 27P, 31P 791 666 37520 56.3 75 14T, 17R, 21P, 27P, 31P 666 2969069 30.6 76 17R, 21P, 27P, 34H 215 297 7370 24.8 77 17R, 21P, 27P, 34H428 145 5398 37.3 78 17R, 21P, 27P, 34R 602 316 8165 25.8 79 17R, 21P,27P, 34R 790 161 3938 24.5 80 14H, 17R, 21P, 27P, 34H 290 139 2141 15.481 14H, 17R, 21P, 27P, 34H 271 130 1727 13.3 82 14R, 17R, 21P, 27P 636215 12730 59.2 83 14R, 17R, 21P, 27P 939 405 16840 41.6 84 14H, 17R,21P, 27P, 34R 743 169 5486 32.5 85 14H, 17R, 21P, 27P, 34R 876 146 388226.6 86 17R, 21P, 27P, 34H 833 298 19157 64.4 89 14E, 17R, 21P, 27P, 35R1160 404 11221 27.8 91 17R, 21P, 27P, 34H 119 40 1477 36.9 92 14H, 17R,21P, 27P 179 85 2378 28.0 95 17R, 21P, 27P, 34R 967 651 21500 33.0 9617R, 21P, 27P, 31P 166 181 3801 21.0 97 17R, 21P, 27P, 34H 568 356 1175033.0 98 17R, 21P, 27P, 34P 91 84 1634 19.5 99 −1G, 1R, 14H, 17R, 21P,27P 348 82 818 10.0 104 14E, 17R, 21P, 27P, 34H, 35E 525 445 7053 15.8105 14E, 17R, 21P, 27P, 34R, 35E 957 703 7426 10.6 106 14E, 17R, 21P,27P, 34P, 35E 121 225 2362 10.5 110 14E, 17R, 21P, 27P, 34P, 35R 326 2788158 29.3 111 17R, 21P, 27P, 34H 580 34 2214 65.1 112 17R, 21P, 27P, 34H1037 28 1087 38.8 113 17R, 21P, 27P, 34H 382 96 5846 60.9 117 14E, 17R,21P, 27P, 34P, 35R 163 376 6380 17.0 118 14E, 17R, 21P, 27P, 34P, 35H179 101 1451 14.4 119 17R, 21P, 27P, 31P, 34P, 35R 880 333 8660 26.0 12414E, 17R, 21P, 27P, 34P, 35H 377 172 2833 16.4 126 14E, 17R, 23P, 34P,35E 1187 5168 89580 17.3 128 14E, 17R, 21P, 27P, 35H 992 425 5575 13.1129 14D, 17R, 21P, 27P, 34P, 35R 281 146 3640 24.9 130 14D, 17R, 21P,27P, 34P, 35R 453 162 7280 44.9 131 14d, 17R, 21P, 27P, 35R 365 383100000 261.1 132 14D, 17R, 21P, 27P, 35R 266 11 318 28.9

TABLE 6c hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 2 14D, 17R, 21P, 27P, 35D 411 182 2998 16.4 19 14E, 17R, 21P, 27P556 307 5321 17.4 24 17R, 21P, 27P 1138 433 10000 23.1 25 17R, 21P, 27P,35E 768 217 10000 46.2 26 17R, 21P, 27P, 35E 532 212 6338 29.9 27 17R,21P, 27P, 35E 837 133 3001 22.6 35 17R, 21P, 27P, 35K 970 364 5459 15.038 17R, 21P, 27P, 35R 249 352 18260 51.9 40 17R, 21P, 27P, 34H 549 1642680 16.4 41 17R, 21P, 27P 427 260 4346 16.7 44 −1K, 1R, 17R, 21P, 27P,35H 275 198 4751 24.0 45 −1K, 1R, 17R, 21P, 27P, 35H 552 594 10100 17.048 17R, 21P, 27P 443 116 1968 17.0 49 17R, 21P, 27P, 31P 1191 106 239022.5 50 17R, 21P, 27P, 34P 38 38 662 17.4 52 14D, 17R, 21P, 27P, 35R 697340 14074 41.4 55 17R, 21P, 27P, 28P, 34P 42 68 731 10.8 57 17R, 21P,27P, 31P, 35H 115 89 3119 35.0 58 17R, 21P, 27P, 34P, 35H 88 47 102821.9 60 17R, 21P, 27P, 35H 695 351 5355 15.3 63 14R, 17R, 21P, 27P, 31P825 37 5131 138.7 64 14R, 17R, 21P, 27P, 31P 444 378 22940 60.7 65 14R,17R, 21P, 27P, 34P 649 242 9331 38.6 66 14H, 17R, 21P, 27P, 35H 396 27542 20.1 68 14H, 17R, 21P, 27P, 34P 88 54 932 17.4 70 14H, 17R, 21P, 27P169 40 715 17.9 72 14A, 17R, 21P, 27P, 31P 172 106 4758 44.9 74 14K,17R, 21P, 27P, 31P 791 666 37520 56.3 75 14T, 17R, 21P, 27P, 31P 666 2969069 30.6 76 17R, 21P, 27P, 34H 215 297 7370 24.8 77 17R, 21P, 27P, 34H428 145 5398 37.3 78 17R, 21P, 27P, 34R 602 316 8165 25.8 79 17R, 21P,27P, 34R 790 161 3938 24.5 82 14R, 17R, 21P, 27P 636 215 12730 59.2 8314R, 17R, 21P, 27P 939 405 16840 41.6 84 14H, 17R, 21P, 27P, 34R 743 1695486 32.5 85 14H, 17R, 21P, 27P, 34R 876 146 3882 26.6 86 17R, 21P, 27P,34H 833 298 19157 64.4 89 14E, 17R, 21P, 27P, 35R 1160 404 11221 27.8 9117R, 21P, 27P, 34H 119 40 1477 36.9 92 14H, 17R, 21P, 27P 179 85 237828.0 95 17R, 21P, 27P, 34R 967 651 21500 33.0 96 17R, 21P, 27P, 31P 166181 3801 21.0 97 17R, 21P, 27P, 34H 568 356 11750 33.0 98 17R, 21P, 27P,34P 91 84 1634 19.5 104 14E, 17R, 21P, 27P, 34H, 35E 525 445 7053 15.8110 14E, 17R, 21P, 27P, 34P, 35R 326 278 8158 29.3 111 17R, 21P, 27P,34H 580 34 2214 65.1 112 17R, 21P, 27P, 34H 1037 28 1087 38.8 113 17R,21P, 27P, 34H 382 96 5846 60.9 117 14E, 17R, 21P, 27P, 34P, 35R 163 3766380 17.0 119 17R, 21P, 27P, 31P, 34P, 35R 880 333 8660 26.0 124 14E,17R, 21P, 27P, 34P, 35H 377 172 2833 16.4 126 14E, 17R, 23P, 34P, 35E1187 5168 89580 17.3 129 14D, 17R, 21P, 27P, 34P, 35R 281 146 3640 24.9130 14D, 17R, 21P, 27P, 34P, 35R 453 162 7280 44.9 131 14d, 17R, 21P,27P, 35R 365 383 100000 261.1 132 14D, 17R, 21P, 27P, 35R 266 11 31828.9

TABLE 6d hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 4 14E, 17R, 21P, 25P, 28P, 29P, 321 60 70 1.2 37P 5 14E, 17R,21P, 26P, 37P 374 162 160 1.0 8 14E, 17R, 21P, 27P, 37P 72 82 87 1.1 1014D, 17R, 21P, 27P, 37P 82 72 70 1.0 11 14E, 17R, 21P, 27P, 35D, 37P 105120 112 0.9 12 14E, 17R, 21P, 27P, 37P 142 101 185 1.8 13 14E, 17R, 21P,27P, 37P 264 213 470 2.2 14 14E, 17R, 21P, 27P, 37P 196 146 238 1.6 1814E, 17R, 21P, 27P, 35H 554 154 742 4.8 20 14E, 17R, 21P, 27P, 37P 21780 285 3.6 21 17R, 21P, 27P 585 148 611 4.1 22 14E, 17R, 21P, 27P, 35E794 270 1026 3.8 33 14E, 17R, 21P, 28P, 35E 915 243 528 2.2 37 14E, 17R,21P, 27P, 29P 970 92 372 4.0 94 14A, 17R, 21P, 27P, 34P 148 70 316 4.5101 −1G, 1R, 14A, 17R, 21P, 27P, 426 109 537 4.9 34H 102 −1G, 1R, 14H,17R, 21P, 27P, 217 62 179 2.9 34P 103 −1G, 1R, 14A, 17R, 21P, 27P, 11470 148 2.1 34P 114 14E, 17R, 21P, 27P, 34P, 37P 214 105 90 0.9 115 14H,17R, 21P, 27P, 34P, 37P 131 52 40 0.8 116 14H, 17R, 21P, 27P, 31P, 34P82 71 345 4.9 123 14D, 17R, 21P, 27P, 34P, 35E 196 288 1115 3.9 125 14E,17R, 21P, 27P, 34P, 35E, 533 132 102 0.8 37P

TABLE 6e hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 4 14E, 17R, 21P, 25P, 28P, 29P, 321 60 70 1.2 37P 5 14E, 17R,21P, 26P, 37P 374 162 160 1.0 8 14E, 17R, 21P, 27P, 37P 72 82 87 1.1 1014D, 17R, 21P, 27P, 37P 82 72 70 1.0 11 14E, 17R, 21P, 27P, 35D, 37P 105120 112 0.9 12 14E, 17R, 21P, 27P, 37P 142 101 185 1.8 13 14E, 17R, 21P,27P, 37P 264 213 470 2.2 14 14E, 17R, 21P, 27P, 37P 196 146 238 1.6 2014E, 17R, 21P, 27P, 37P 217 80 285 3.6 22 14E, 17R, 21P, 27P, 35E 794270 1026 3.8 33 14E, 17R, 21P, 28P, 35E 915 243 528 2.2 102 −1G, 1R,14H, 17R, 21P, 27P, 217 62 179 2.9 34P 103 −1G, 1R, 14A, 17R, 21P, 27P,114 70 148 2.1 34P 114 14E, 17R, 21P, 27P, 34P, 37P 214 105 90 0.9 11514H, 17R, 21P, 27P, 34P, 37P 131 52 40 0.8 123 14D, 17R, 21P, 27P, 34P,35E 196 288 1115 3.9 125 14E, 17R, 21P, 27P, 34P, 35E, 533 132 102 0.837P

TABLE 6f hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 18 14E, 17R, 21P, 27P, 35H 554 154 742 4.8 22 14E, 17R, 21P, 27P,35E 794 270 1026 3.8 23 17R, 21P, 27P, 35E 871 340 3025 8.9 25 17R, 21P,27P, 35E 768 217 10000 46.2 26 17R, 21P, 27P, 35E 532 212 6338 29.9 2717R, 21P, 27P, 35E 837 133 3001 22.6 28 17R, 21P, 27P, 31P, 35E 610 2202033 9.2 29 17R, 21P, 27P, 34P, 35E 577 99 857 8.7 30 14H, 17R, 21P,27P, 35E 919 134 1677 12.6 33 14E, 17R, 21P, 28P, 35E 915 243 528 2.2 44−1K, 1R, 17R, 21P, 27P, 35H 275 198 4751 24.0 45 −1K, 1R, 17R, 21P, 27P,35H 552 594 10100 17.0 46 −1G, 1R, 17R, 21P, 27P 195 88 899 10.2 47 −1G,1R, 17R, 21P, 27P, 35H 344 222 1322 6.0 57 17R, 21P, 27P, 31P, 35H 11589 3119 35.0 58 17R, 21P, 27P, 34P, 35H 88 47 1028 21.9 60 17R, 21P,27P, 35H 695 351 5355 15.3 66 14H, 17R, 21P, 27P, 35H 396 27 542 20.1104 14E, 17R, 21P, 27P, 34H, 35E 525 445 7053 15.8 105 14E, 17R, 21P,27P, 34R, 35E 957 703 7426 10.6 106 14E, 17R, 21P, 27P, 34P, 35E 121 2252362 10.5 107 14E, 17R, 21P, 27P, 34H, 35E 387 405 2541 6.3 108 14E,17R, 21P, 27P, 34R, 35E 232 421 2745 6.5 109 14E, 17R, 21P, 27P, 34P,35E 140 161 841 5.2 118 14E, 17R, 21P, 27P, 34P, 35H 179 101 1451 14.4120 14S, 17R, 21P, 27P, 34P, 35E 76 109 887 8.1 121 14E, 17R, 21P, 31P,34P, 35E 69 222 1280 5.8 122 14D, 17R, 21P, 27P, 34P, 35E 172 159 8435.3 123 14D, 17R, 21P, 27P, 34P, 35E 196 288 1115 3.9 124 14E, 17R, 21P,27P, 34P, 35H 377 172 2833 16.4 125 14E, 17R, 21P, 27P, 34P, 35E, 533132 102 0.8 37P 126 14E, 17R, 23P, 34P, 35E 1187 5168 89580 17.3 12814E, 17R, 21P, 27P, 35H 992 425 5575 13.1

TABLE 6g hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 4 14E, 17R, 21P, 25P, 28P, 29P, 321 60 70 1.2 37P 5 14E, 17R,21P, 26P, 37P 374 162 160 1.0 8 14E, 17R, 21P, 27P, 37P 72 82 87 1.1 1014D, 17R, 21P, 27P, 37P 82 72 70 1.0 11 14E, 17R, 21P, 27P, 35D, 37P 105120 112 0.9 12 14E, 17R, 21P, 27P, 37P 142 101 185 1.8 13 14E, 17R, 21P,27P, 37P 264 213 470 2.2 14 14E, 17R, 21P, 27P, 37P 196 146 238 1.6 2014E, 17R, 21P, 27P, 37P 217 80 285 3.6 114 14E, 17R, 21P, 27P, 34P, 37P214 105 90 0.9 115 14H, 17R, 21P, 27P, 34P, 37P 131 52 40 0.8 125 14E,17R, 21P, 27P, 34P, 35E, 533 132 102 0.8 37P

TABLE 6h hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 17 14E, 17R, 21P, 27P, 34H 878 268 2351 8.8 40 17R, 21P, 27P, 34H549 164 2680 16.4 86 17R, 21P, 27P, 34H 833 298 19157 64.4 87 14E, 17R,21P, 27P, 34H 633 285 1095 3.8 91 17R, 21P, 27P, 34H 119 40 1477 36.9 9214H, 17R, 21P, 27P 179 85 2378 28.0 93 14A, 17R, 21P, 27P, 34H 176 1181145 9.7 97 17R, 21P, 27P, 34H 568 356 11750 33.0 100 −1G, 1R, 14H, 17R,21P, 27P, 1015 253 1726 6.8 34H 101 −1G, 1R, 14A, 17R, 21P, 27P, 426 109537 4.9 34H 104 14E, 17R, 21P, 27P, 34H, 35E 525 445 7053 15.8 107 14E,17R, 21P, 27P, 34H, 35E 387 405 2541 6.3 111 17R, 21P, 27P, 34H 580 342214 65.1 112 17R, 21P, 27P, 34H 1037 28 1087 38.8 113 17R, 21P, 27P,34H 382 96 5846 60.9

TABLE 6i hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 4 14E, 17R, 21P, 25P, 28P, 29P, 321 60 70 1.2 37P 5 14E, 17R,21P, 26P, 37P 374 162 160 1.0 6 14E, 17R, 21P, 25P, 28P, 29P 996 128 7295.7 7 14E, 17R, 21P, 26P 674 255 1156 4.5 8 14E, 17R, 21P, 27P, 37P 7282 87 1.1 9 14E, 17R, 21P, 27P 143 175 1288 7.4 11 14E, 17R, 21P, 27P,35D, 37P 105 120 112 0.9 12 14E, 17R, 21P, 27P, 37P 142 101 185 1.8 1314E, 17R, 21P, 27P, 37P 264 213 470 2.2 14 14E, 17R, 21P, 27P, 37P 196146 238 1.6 15 14E, 17R, 21P, 27P 597 386 3432 8.9 16 14E, 17R, 21P,27P, 35R 894 363 2215 6.1 17 14E, 17R, 21P, 27P, 34H 878 268 2351 8.8 1814E, 17R, 21P, 27P, 35H 554 154 742 4.8 19 14E, 17R, 21P, 27P 556 3075321 17.4 20 14E, 17R, 21P, 27P, 37P 217 80 285 3.6 22 14E, 17R, 21P,27P, 35E 794 270 1026 3.8 31 14E, 17R, 21P, 27P, 31P 204 112 717 6.4 3214E, 17R, 21P, 27P, 34P 100 50 327 6.6 33 14E, 17R, 21P, 28P, 35E 915243 528 2.2 36 14E, 17R, 21P, 27P, 34K 403 189 1280 6.8 37 14E, 17R,21P, 27P, 29P 970 92 372 4.0 51 14E, 17R, 21P, 27P, 35R 828 372 521614.0 87 14E, 17R, 21P, 27P, 34H 633 285 1095 3.8 88 14E, 17R, 21P, 27P,34R 750 773 6555 8.5 89 14E, 17R, 21P, 27P, 35R 1160 404 11221 27.8 10414E, 17R, 21P, 27P, 34H, 35E 525 445 7053 15.8 105 14E, 17R, 21P, 27P,34R, 35E 957 703 7426 10.6 106 14E, 17R, 21P, 27P, 34P, 35E 121 225 236210.5 107 14E, 17R, 21P, 27P, 34H, 35E 387 405 2541 6.3 108 14E, 17R,21P, 27P, 34R, 35E 232 421 2745 6.5 109 14E, 17R, 21P, 27P, 34P, 35E 140161 841 5.2 110 14E, 17R, 21P, 27P, 34P, 35R 326 278 8158 29.3 114 14E,17R, 21P, 27P, 34P, 37P 214 105 90 0.9 117 14E, 17R, 21P, 27P, 34P, 35R163 376 6380 17.0 118 14E, 17R, 21P, 27P, 34P, 35H 179 101 1451 14.4 12114E, 17R, 21P, 31P, 34P, 35E 69 222 1280 5.8 124 14E, 17R, 21P, 27P,34P, 35H 377 172 2833 16.4 125 14E, 17R, 21P, 27P, 34P, 35E, 533 132 1020.8 37P 126 14E, 17R, 23P, 34P, 35E 1187 5168 89580 17.3 127 14E, 17R,21P, 27P, 34P, 37F 152 216 2140 9.9 128 14E, 17R, 21P, 27P, 35H 992 4255575 13.1

TABLE 6j hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 2 14D, 17R, 21P, 27P, 35D 411 182 2998 16.4 8 14E, 17R, 21P, 27P,37P 72 82 87 1.1 9 14E, 17R, 21P, 27P 143 175 1288 7.4 10 14D, 17R, 21P,27P, 37P 82 72 70 1.0 11 14E, 17R, 21P, 27P, 35D, 37P 105 120 112 0.9 1214E, 17R, 21P, 27P, 37P 142 101 185 1.8 13 14E, 17R, 21P, 27P, 37P 264213 470 2.2 14 14E, 17R, 21P, 27P, 37P 196 146 238 1.6 15 14E, 17R, 21P,27P 597 386 3432 8.9 16 14E, 17R, 21P, 27P, 35R 894 363 2215 6.1 17 14E,17R, 21P, 27P, 34H 878 268 2351 8.8 18 14E, 17R, 21P, 27P, 35H 554 154742 4.8 19 14E, 17R, 21P, 27P 556 307 5321 17.4 20 14E, 17R, 21P, 27P,37P 217 80 285 3.6 21 17R, 21P, 27P 585 148 611 4.1 22 14E, 17R, 21P,27P, 35E 794 270 1026 3.8 23 17R, 21P, 27P, 35E 871 340 3025 8.9 24 17R,21P, 27P 1138 433 10000 23.1 25 17R, 21P, 27P, 35E 768 217 10000 46.2 2617R, 21P, 27P, 35E 532 212 6338 29.9 27 17R, 21P, 27P, 35E 837 133 300122.6 28 17R, 21P, 27P, 31P, 35E 610 220 2033 9.2 29 17R, 21P, 27P, 34P,35E 577 99 857 8.7 30 14H, 17R, 21P, 27P, 35E 919 134 1677 12.6 31 14E,17R, 21P, 27P, 31P 204 112 717 6.4 32 14E, 17R, 21P, 27P, 34P 100 50 3276.6 34 17R, 21P, 27P, 35K 1139 313 2615 8.4 35 17R, 21P, 27P, 35K 970364 5459 15.0 36 14E, 17R, 21P, 27P, 34K 403 189 1280 6.8 37 14E, 17R,21P, 27P, 29P 970 92 372 4.0 38 17R, 21P, 27P, 35R 249 352 18260 51.9 3917R, 21P, 27P, 34R 665 217 2522 11.6 40 17R, 21P, 27P, 34H 549 164 268016.4 41 17R, 21P, 27P 427 260 4346 16.7 42 17R, 21P, 27P 264 146 197513.5 43 17R, 21P, 27P 76 141 920 6.5 44 −1K, 1R, 17R, 21P, 27P, 35H 275198 4751 24.0 45 −1K, 1R, 17R, 21P, 27P, 35H 552 594 10100 17.0 46 −1G,1R, 17R, 21P, 27P 195 88 899 10.2 47 −1G, 1R, 17R, 21P, 27P, 35H 344 2221322 6.0 48 17R, 21P, 27P 443 116 1968 17.0 49 17R, 21P, 27P, 31P 1191106 2390 22.5 50 17R, 21P, 27P, 34P 38 38 662 17.4 51 14E, 17R, 21P,27P, 35R 828 372 5216 14.0 52 14D, 17R, 21P, 27P, 35R 697 340 14074 41.453 17R, 21P, 27P, 28P, 31P 52 64 625 9.8 54 17R, 21P, 27P, 29P, 31P 30103 987 9.6 55 17R, 21P, 27P, 28P, 34P 42 68 731 10.8 56 17R, 21P, 27P,29P, 34P 49 102 506 5.0 57 17R, 21P, 27P, 31P, 35H 115 89 3119 35.0 5817R, 21P, 27P, 34P, 35H 88 47 1028 21.9 60 17R, 21P, 27P, 35H 695 3515355 15.3 61 14H, 17R, 21P, 27P, 31P 122 51 554 10.9 62 14H, 17R, 21P,27P, 31P 98 44 539 12.3 63 14R, 17R, 21P, 27P, 31P 825 37 5131 138.7 6414R, 17R, 21P, 27P, 31P 444 378 22940 60.7 65 14R, 17R, 21P, 27P, 34P649 242 9331 38.6 66 14H, 17R, 21P, 27P, 35H 396 27 542 20.1 67 14H,17R, 21P, 27P, 34P 90 69 354 5.2 68 14H, 17R, 21P, 27P, 34P 88 54 93217.4 69 14H, 17R, 21P, 27P 133 94 1248 13.3 70 14H, 17R, 21P, 27P 169 40715 17.9 71 14G, 17R, 21P, 27P, 31P 48 56 527 9.4 72 14A, 17R, 21P, 27P,31P 172 106 4758 44.9 73 14S, 17R, 21P, 27P, 31P 104 85 961 11.3 74 14K,17R, 21P, 27P, 31P 791 666 37520 56.3 75 14T, 17R, 21P, 27P, 31P 666 2969069 30.6 76 17R, 21P, 27P, 34H 215 297 7370 24.8 77 17R, 21P, 27P, 34H428 145 5398 37.3 78 17R, 21P, 27P, 34R 602 316 8165 25.8 79 17R, 21P,27P, 34R 790 161 3938 24.5 80 14H, 17R, 21P, 27P, 34H 290 139 2141 15.481 14H, 17R, 21P, 27P, 34H 271 130 1727 13.3 82 14R, 17R, 21P, 27P 636215 12730 59.2 83 14R, 17R, 21P, 27P 939 405 16840 41.6 84 14H, 17R,21P, 27P, 34R 743 169 5486 32.5 85 14H, 17R, 21P, 27P, 34R 876 146 388226.6 86 17R, 21P, 27P, 34H 833 298 19157 64.4 87 14E, 17R, 21P, 27P, 34H633 285 1095 3.8 88 14E, 17R, 21P, 27P, 34R 750 773 6555 8.5 89 14E,17R, 21P, 27P, 35R 1160 404 11221 27.8 90 14H, 17R, 21P, 27P 61 33 2367.2 91 17R, 21P, 27P, 34H 119 40 1477 36.9 92 14H, 17R, 21P, 27P 179 852378 28.0 93 14A, 17R, 21P, 27P, 34H 176 118 1145 9.7 94 14A, 17R, 21P,27P, 34P 148 70 316 4.5 95 17R, 21P, 27P, 34R 967 651 21500 33.0 96 17R,21P, 27P, 31P 166 181 3801 21.0 97 17R, 21P, 27P, 34H 568 356 11750 33.098 17R, 21P, 27P, 34P 91 84 1634 19.5 99 −1G, 1R, 14H, 17R, 21P, 27P 34882 818 10.0 100 −1G, 1R, 14H, 17R, 21P, 27P, 1015 253 1726 6.8 34H 101−1G, 1R, 14A, 17R, 21P, 27P, 426 109 537 4.9 34H 102 −1G, 1R, 14H, 17R,21P, 27P, 217 62 179 2.9 34P 103 −1G, 1R, 14A, 17R, 21P, 27P, 114 70 1482.1 34P 104 14E, 17R, 21P, 27P, 34H, 35E 525 445 7053 15.8 105 14E, 17R,21P, 27P, 34R, 35E 957 703 7426 10.6 106 14E, 17R, 21P, 27P, 34P, 35E121 225 2362 10.5 107 14E, 17R, 21P, 27P, 34H, 35E 387 405 2541 6.3 10814E, 17R, 21P, 27P, 34R, 35E 232 421 2745 6.5 109 14E, 17R, 21P, 27P,34P, 35E 140 161 841 5.2 110 14E, 17R, 21P, 27P, 34P, 35R 326 278 815829.3 111 17R, 21P, 27P, 34H 580 34 2214 65.1 112 17R, 21P, 27P, 34H 103728 1087 38.8 113 17R, 21P, 27P, 34H 382 96 5846 60.9 114 14E, 17R, 21P,27P, 34P, 37P 214 105 90 0.9 115 14H, 17R, 21P, 27P, 34P, 37P 131 52 400.8 116 14H, 17R, 21P, 27P, 31P, 34P 82 71 345 4.9 117 14E, 17R, 21P,27P, 34P, 35R 163 376 6380 17.0 118 14E, 17R, 21P, 27P, 34P, 35H 179 1011451 14.4 119 17R, 21P, 27P, 31P, 34P, 35R 880 333 8660 26.0 120 14S,17R, 21P, 27P, 34P, 35E 76 109 887 8.1 122 14D, 17R, 21P, 27P, 34P, 35E172 159 843 5.3 123 14D, 17R, 21P, 27P, 34P, 35E 196 288 1115 3.9 12414E, 17R, 21P, 27P, 34P, 35H 377 172 2833 16.4 125 14E, 17R, 21P, 27P,34P, 35E, 533 132 102 0.8 37P 127 14E, 17R, 21P, 27P, 34P, 37F 152 2162140 9.9 128 14E, 17R, 21P, 27P, 35H 992 425 5575 13.1 129 14D, 17R,21P, 27P, 34P, 35R 281 146 3640 24.9 130 14D, 17R, 21P, 27P, 34P, 35R453 162 7280 44.9 131 14d, 17R, 21P, 27P, 35R 365 383 100000 261.1 13214D, 17R, 21P, 27P, 35R 266 11 318 28.9

TABLE 6k hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 2 14D, 17R, 21P, 27P, 35D 411 182 2998 16.4 15 14E, 17R, 21P, 27P597 386 3432 8.9 16 14E, 17R, 21P, 27P, 35R 894 363 2215 6.1 17 14E,17R, 21P, 27P, 34H 878 268 2351 8.8 19 14E, 17R, 21P, 27P 556 307 532117.4 23 17R, 21P, 27P, 35E 871 340 3025 8.9 24 17R, 21P, 27P 1138 43310000 23.1 25 17R, 21P, 27P, 35E 768 217 10000 46.2 26 17R, 21P, 27P,35E 532 212 6338 29.9 27 17R, 21P, 27P, 35E 837 133 3001 22.6 28 17R,21P, 27P, 31P, 35E 610 220 2033 9.2 29 17R, 21P, 27P, 34P, 35E 577 99857 8.7 30 14H, 17R, 21P, 27P, 35E 919 134 1677 12.6 31 14E, 17R, 21P,27P, 31P 204 112 717 6.4 32 14E, 17R, 21P, 27P, 34P 100 50 327 6.6 3417R, 21P, 27P, 35K 1139 313 2615 8.4 35 17R, 21P, 27P, 35K 970 364 545915.0 36 14E, 17R, 21P, 27P, 34K 403 189 1280 6.8 38 17R, 21P, 27P, 35R249 352 18260 51.9 39 17R, 21P, 27P, 34R 665 217 2522 11.6 40 17R, 21P,27P, 34H 549 164 2680 16.4 41 17R, 21P, 27P 427 260 4346 16.7 42 17R,21P, 27P 264 146 1975 13.5 43 17R, 21P, 27P 76 141 920 6.5 44 −1K, 1R,17R, 21P, 27P, 35H 275 198 4751 24.0 45 −1K, 1R, 17R, 21P, 27P, 35H 552594 10100 17.0 46 −1G, 1R, 17R, 21P, 27P 195 88 899 10.2 47 −1G, 1R,17R, 21P, 27P, 35H 344 222 1322 6.0 48 17R, 21P, 27P 443 116 1968 17.049 17R, 21P, 27P, 31P 1191 106 2390 22.5 50 17R, 21P, 27P, 34P 38 38 66217.4 51 14E, 17R, 21P, 27P, 35R 828 372 5216 14.0 52 14D, 17R, 21P, 27P,35R 697 340 14074 41.4 53 17R, 21P, 27P, 28P, 31P 52 64 625 9.8 54 17R,21P, 27P, 29P, 31P 30 103 987 9.6 55 17R, 21P, 27P, 28P, 34P 42 68 73110.8 56 17R, 21P, 27P, 29P, 34P 49 102 506 5.0 57 17R, 21P, 27P, 31P,35H 115 89 3119 35.0 58 17R, 21P, 27P, 34P, 35H 88 47 1028 21.9 60 17R,21P, 27P, 35H 695 351 5355 15.3 61 14H, 17R, 21P, 27P, 31P 122 51 55410.9 62 14H, 17R, 21P, 27P, 31P 98 44 539 12.3 63 14R, 17R, 21P, 27P,31P 825 37 5131 138.7 64 14R, 17R, 21P, 27P, 31P 444 378 22940 60.7 6514R, 17R, 21P, 27P, 34P 649 242 9331 38.6 66 14H, 17R, 21P, 27P, 35H 39627 542 20.1 67 14H, 17R, 21P, 27P, 34P 90 69 354 5.2 68 14H, 17R, 21P,27P, 34P 88 54 932 17.4 69 14H, 17R, 21P, 27P 133 94 1248 13.3 70 14H,17R, 21P, 27P 169 40 715 17.9 71 14G, 17R, 21P, 27P, 31P 48 56 527 9.472 14A, 17R, 21P, 27P, 31P 172 106 4758 44.9 73 14S, 17R, 21P, 27P, 31P104 85 961 11.3 74 14K, 17R, 21P, 27P, 31P 791 666 37520 56.3 75 14T,17R, 21P, 27P, 31P 666 296 9069 30.6 76 17R, 21P, 27P, 34H 215 297 737024.8 77 17R, 21P, 27P, 34H 428 145 5398 37.3 78 17R, 21P, 27P, 34R 602316 8165 25.8 79 17R, 21P, 27P, 34R 790 161 3938 24.5 80 14H, 17R, 21P,27P, 34H 290 139 2141 15.4 81 14H, 17R, 21P, 27P, 34H 271 130 1727 13.382 14R, 17R, 21P, 27P 636 215 12730 59.2 83 14R, 17R, 21P, 27P 939 40516840 41.6 84 14H, 17R, 21P, 27P, 34R 743 169 5486 32.5 85 14H, 17R,21P, 27P, 34R 876 146 3882 26.6 86 17R, 21P, 27P, 34H 833 298 19157 64.488 14E, 17R, 21P, 27P, 34R 750 773 6555 8.5 89 14E, 17R, 21P, 27P, 35R1160 404 11221 27.8 90 14H, 17R, 21P, 27P 61 33 236 7.2 91 17R, 21P,27P, 34H 119 40 1477 36.9 92 14H, 17R, 21P, 27P 179 85 2378 28.0 93 14A,17R, 21P, 27P, 34H 176 118 1145 9.7 95 17R, 21P, 27P, 34R 967 651 2150033.0 96 17R, 21P, 27P, 31P 166 181 3801 21.0 97 17R, 21P, 27P, 34H 568356 11750 33.0 98 17R, 21P, 27P, 34P 91 84 1634 19.5 99 −1G, 1R, 14H,17R, 21P, 27P 348 82 818 10.0 100 −1G, 1R, 14H, 17R, 21P, 27P, 1015 2531726 6.8 34H 104 14E, 17R, 21P, 27P, 34H, 35E 525 445 7053 15.8 105 14E,17R, 21P, 27P, 34R, 35E 957 703 7426 10.6 106 14E, 17R, 21P, 27P, 34P,35E 121 225 2362 10.5 107 14E, 17R, 21P, 27P, 34H, 35E 387 405 2541 6.3108 14E, 17R, 21P, 27P, 34R, 35E 232 421 2745 6.5 109 14E, 17R, 21P,27P, 34P, 35E 140 161 841 5.2 110 14E, 17R, 21P, 27P, 34P, 35R 326 2788158 29.3 111 17R, 21P, 27P, 34H 580 34 2214 65.1 112 17R, 21P, 27P, 34H1037 28 1087 38.8 113 17R, 21P, 27P, 34H 382 96 5846 60.9 117 14E, 17R,21P, 27P, 34P, 35R 163 376 6380 17.0 118 14E, 17R, 21P, 27P, 34P, 35H179 101 1451 14.4 119 17R, 21P, 27P, 31P, 34P, 35R 880 333 8660 26.0 12014S, 17R, 21P, 27P, 34P, 35E 76 109 887 8.1 122 14D, 17R, 21P, 27P, 34P,35E 172 159 843 5.3 124 14E, 17R, 21P, 27P, 34P, 35H 377 172 2833 16.4127 14E, 17R, 21P, 27P, 34P, 37F 152 216 2140 9.9 128 14E, 17R, 21P,27P, 35H 992 425 5575 13.1 129 14D, 17R, 21P, 27P, 34P, 35R 281 146 364024.9 130 14D, 17R, 21P, 27P, 34P, 35R 453 162 7280 44.9 131 14d, 17R,21P, 27P, 35R 365 383 100000 261.1 132 14D, 17R, 21P, 27P, 35R 266 11318 28.9

TABLE 6l hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 8 14E, 17R, 21P, 27P, 37P 72 82 87 1.1 10 14D, 17R, 21P, 27P, 37P82 72 70 1.0 11 14E, 17R, 21P, 27P, 35D, 37P 105 120 112 0.9 12 14E,17R, 21P, 27P, 37P 142 101 185 1.8 13 14E, 17R, 21P, 27P, 37P 264 213470 2.2 14 14E, 17R, 21P, 27P, 37P 196 146 238 1.6 18 14E, 17R, 21P,27P, 35H 554 154 742 4.8 20 14E, 17R, 21P, 27P, 37P 217 80 285 3.6 2117R, 21P, 27P 585 148 611 4.1 22 14E, 17R, 21P, 27P, 35E 794 270 10263.8 37 14E, 17R, 21P, 27P, 29P 970 92 372 4.0 87 14E, 17R, 21P, 27P, 34H633 285 1095 3.8 88 14E, 17R, 21P, 27P, 34R 750 773 6555 8.5 94 14A,17R, 21P, 27P, 34P 148 70 316 4.5 101 −1G, 1R, 14A, 17R, 21P, 27P, 426109 537 4.9 34H 102 −1G, 1R, 14H, 17R, 21P, 27P, 217 62 179 2.9 34P 103−1G, 1R, 14A, 17R, 21P, 27P, 114 70 148 2.1 34P 114 14E, 17R, 21P, 27P,34P, 37P 214 105 90 0.9 115 14H, 17R, 21P, 27P, 34P, 37P 131 52 40 0.8116 14H, 17R, 21P, 27P, 31P, 34P 82 71 345 4.9 123 14D, 17R, 21P, 27P,34P, 35E 196 288 1115 3.9 125 14E, 17R, 21P, 27P, 34P, 35E, 533 132 1020.8 37P 127 14E, 17R, 21P, 27P, 34P, 37F 152 216 2140 9.9

TABLE 6m hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 16 14E, 17R, 21P, 27P, 35R 894 363 2215 6.1 38 17R, 21P, 27P, 35R249 352 18260 51.9 89 14E, 17R, 21P, 27P, 35R 1160 404 11221 27.8 11014E, 17R, 21P, 27P, 34P, 35R 326 278 8158 29.3 117 14E, 17R, 21P, 27P,34P, 35R 163 376 6380 17.0 119 17R, 21P, 27P, 31P, 34P, 35R 880 333 866026.0 129 14D, 17R, 21P, 27P, 34P, 35R 281 146 3640 24.9 130 14D, 17R,21P, 27P, 34P, 35R 453 162 7280 44.9 131 14d, 17R, 21P, 27P, 35R 365 383100000 261.1 132 14D, 17R, 21P, 27P, 35R 266 11 318 28.9

TABLE 6n hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 18 14E, 17R, 21P, 27P, 35H 554 154 742 4.8 44 −1K, 1R, 17R, 21P,27P, 35H 275 198 4751 24.0 45 −1K, 1R, 17R, 21P, 27P, 35H 552 594 1010017.0 47 −1G, 1R, 17R, 21P, 27P, 35H 344 222 1322 6.0 57 17R, 21P, 27P,31P, 35H 115 89 3119 35.0 58 17R, 21P, 27P, 34P, 35H 88 47 1028 21.9 6017R, 21P, 27P, 35H 695 351 5355 15.3 66 14H, 17R, 21P, 27P, 35H 396 27542 20.1 118 14E, 17R, 21P, 27P, 34P, 35H 179 101 1451 14.4 124 14E,17R, 21P, 27P, 34P, 35H 377 172 2833 16.4 128 14E, 17R, 21P, 27P, 35H992 425 5575 13.1

TABLE 6o hAmylin- hAmylin- hCTR R bind R funct. funct. Ratio IC50 EC50EC50 hCT/hAmylin Example no. Sequence modifications (pM) (pM) (pM)funct. 44 −1K, 1R, 17R, 21P, 27P, 35H 275 198 4751 24.0 45 −1K, 1R, 17R,21P, 27P, 35H 552 594 10100 17.0 57 17R, 21P, 27P, 31P, 35H 115 89 311935.0 58 17R, 21P, 27P, 34P, 35H 88 47 1028 21.9 60 17R, 21P, 27P, 35H695 351 5355 15.3 66 14H, 17R, 21P, 27P, 35H 396 27 542 20.1 118 14E,17R, 21P, 27P, 34P, 35H 179 101 1451 14.4 124 14E, 17R, 21P, 27P, 34P,35H 377 172 2833 16.4 128 14E, 17R, 21P, 27P, 35H 992 425 5575 13.1

Binding to Rat Amylin Receptors and Rat Calcitonin Receptors

The in vitro data regarding binding to rat amylin receptors and ratcalcitonin receptors and the corresponding selectivity values are shownin Table 7 (below). For ease of reference, the human binding data arealso included.

Table 7 discloses compounds that have a hAmylinR IC50 value of less than1200 pM and indicates values for rat binding selectivity of at least 10or less than 10. Preferred compounds have a rat binding selectivity ofat least 10. These preferred compounds are shown in Table 7a. In Tables7 and 7a we have also included the human ratios for comparison purposes.As before a ratio of hCT/hAmylin binding of at least 10 is preferred.Table 7b presents those preferred compounds. Details of the albuminbinding moiety, linker and acylation sites have been removed from theseTables. For full structural information please consult the entry with acorresponding compound number in Table 2. Further details regarding thecompounds, such as IUPAC nomenclature may be found in Table 14.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7 and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 7 and table 4a. In one embodiment the amylin polypeptide accordingto the present invention is selected from the compounds which are incommon between the presented compounds of in table 7 and table 4b. Inone embodiment the amylin polypeptide according to the present inventionis selected from the compounds which are in common between the presentedcompounds of in table 7 and table 4a. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds which are in common between the presented compounds of intable 7 and table 4c. In one embodiment the amylin polypeptide accordingto the present invention is selected from the compounds which are incommon between the presented compounds of in table 7 and table 5. In oneembodiment the amylin polypeptide according to the present invention isselected from the compounds which are in common between the presentedcompounds of in table 7 and table

5a. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7 and table 5b. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 7 and table 5c. In one embodiment the amylin polypeptide accordingto the present invention is selected from the compounds which are incommon between the presented compounds of in table 7 and table 8. In oneembodiment the amylin polypeptide according to the present invention isselected from the compounds which are in common between the presentedcompounds of in table 7 and table 8a. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds which are in common between the presented compounds of intable 7 and table 9. In one embodiment the amylin polypeptide accordingto the present invention is selected from the compounds which are incommon between the presented compounds of in table 7 and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7a and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 7a and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 7a and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7a and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 7a and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 7a and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7a and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 7a and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 7a and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7a and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 7a and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 7a and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7a and table 9a.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7b and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 7b and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 7b and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7b and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 7b and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 7b and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7b and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 7b and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 7b and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7b and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 7b and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 7b and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7b and table 9a

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7c and table 4. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 7c and table 4a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 7c and table4b. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7c and table 4a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 7c and table 4c. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 7c and table5. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7c and table 5a. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 7c and table 5b. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 7c and table5c. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7c and table 8. In one embodiment theamylin polypeptide according to the present invention is selected fromthe compounds which are in common between the presented compounds of intable 7c and table 8a. In one embodiment the amylin polypeptideaccording to the present invention is selected from the compounds whichare in common between the presented compounds of in table 7c and table9. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds which are in common between thepresented compounds of in table 7c and table 9a

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 7, exceptthe compounds presented in table 6d. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 7, except the compounds presented in table6e. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 7, exceptthe compounds presented in table 6f. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 7, except the compounds presented in table6h. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 7, exceptthe compounds presented in table 6l. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 7, except the compounds presented in table6o.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 7a, exceptthe compounds presented in table 6d. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 7a, except the compounds presented in table6e. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 7a, exceptthe compounds presented in table 6f. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 7a, except the compounds presented in table6h. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 7a, exceptthe compounds presented in table 6l. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 7a, except the compounds presented in table6o.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 7b, exceptthe compounds presented in table 6d. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 7b, except the compounds presented in table6e. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 7b, exceptthe compounds presented in table 6f. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 7b, except the compounds presented in table6h. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 7b, exceptthe compounds presented in table 6l. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 7b, except the compounds presented in table6o.

In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 7c, exceptthe compounds presented in table 6d. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 7c, except the compounds presented in table6e. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 7c, exceptthe compounds presented in table 6f. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 7c, except the compounds presented in table6h. In one embodiment the amylin polypeptide according to the presentinvention is selected from the compounds presented in table 7c, exceptthe compounds presented in table 6l. In one embodiment the amylinpolypeptide according to the present invention is selected from thecompounds presented in table 7c, except the compounds presented in table6o.

TABLE 7 rAmylin- rCTR R bind bind Ratio Ratio IC50 IC50 rCT/rAmylinhCT/hAmylin Example no. Sequence modifications (pM) (pM) binding binding1 14D, 17R, 21P, 26P, 35D 1300 135100 103.9 27.6 2 14D, 17R, 21P, 27P,35D 295 107798 365.7 47.5 3 14D, 17R, 22P, 26P, 35D 1002 16748 16.7 17.34 14E, 17R, 21P, 25P, 28P, 29P, 1305 4051 3.1 2.1 37P 5 14E, 17R, 21P,26P, 37P 1296 4652 3.6 1.4 6 14E, 17R, 21P, 25P, 28P, 29P 2373 5155021.7 20.0 7 14E, 17R, 21P, 26P 1125 47250 42.0 16.5 8 14E, 17R, 21P,27P, 37P 0.5 9 14E, 17R, 21P, 27P 8.0 10 14D, 17R, 21P, 27P, 37P 1.2 1114E, 17R, 21P, 27P, 35D, 37P 1.0 12 14E, 17R, 21P, 27P, 37P 544 2709 5.02.5 13 14E, 17R, 21P, 27P, 37P 1.2 14 14E, 17R, 21P, 27P, 37P 2.2 1514E, 17R, 21P, 27P 26.0 16 14E, 17R, 21P, 27P, 35R 1210 55220 45.6 19.117 14E, 17R, 21P, 27P, 34H 2710 97230 35.9 12.5 18 14E, 17R, 21P, 27P,35H 476 13000 27.3 9.2 19 14E, 17R, 21P, 27P 1022 95610 93.6 36.7 2014E, 17R, 21P, 27P, 37P 696 4430 6.4 3.6 21 17R, 21P, 27P 1484 2793518.8 24.4 22 14E, 17R, 21P, 27P, 35E 2189 62460 28.5 12.3 23 17R, 21P,27P, 35E 1120 79870 71.3 25.0 24 17R, 21P, 27P 3006 349700 116.3 90.0 2517R, 21P, 27P, 35E 3485 131300 37.7 56.5 26 17R, 21P, 27P, 35E 491151700 309.2 47.5 27 17R, 21P, 27P, 35E 614 90190 146.8 41.3 28 17R,21P, 27P, 31P, 35E 1224 54897 44.9 20.5 29 17R, 21P, 27P, 34P, 35E 32221560 67.0 13.9 30 14H, 17R, 21P, 27P, 35E 3143 113600 36.1 23.6 31 14E,17R, 21P, 27P, 31P 619 26510 42.8 16.0 32 14E, 17R, 21P, 27P, 34P 1765976 34.0 10.9 33 14E, 17R, 21P, 28P, 35E 2295 28885 12.6 3.9 34 17R,21P, 27P, 35K 1715 89170 52.0 64.4 35 17R, 21P, 27P, 35K 948 61740 65.150.3 36 14E, 17R, 21P, 27P, 34K 1856 60060 32.4 15.7 37 14E, 17R, 21P,27P, 29P 514 7354 14.3 2.3 38 17R, 21P, 27P, 35R 383 38020 99.2 84.9 3917R, 21P, 27P, 34R 1770 96440 54.5 29.0 40 17R, 21P, 27P, 34H 1498 6924846.2 31.1 41 17R, 21P, 27P 1371 74090 54.0 49.9 42 17R, 21P, 27P 60315340 25.4 30.7 43 17R, 21P, 27P 110 7601 69.1 34.7 44 −1K, 1R, 17R,21P, 27P, 35H 369 19650 53.3 17.7 45 −1K, 1R, 17R, 21P, 27P, 35H 62341790 67.1 26.8 46 −1G, 1R, 17R, 21P, 27P 330 46780 141.8 48.9 47 −1G,1R, 17R, 21P, 27P, 35H 203 17110 84.3 44.9 48 17R, 21P, 27P 558 112300201.3 69.7 49 17R, 21P, 27P, 31P 1078 51410 47.7 10.8 50 17R, 21P, 27P,34P 69 5634 81.7 36.0 51 14E, 17R, 21P, 27P, 35R 523 61963 118.6 37.5 5214D, 17R, 21P, 27P, 35R 335 159464 476.7 81.6 53 17R, 21P, 27P, 28P, 31P84 10930 130.1 103.5 54 17R, 21P, 27P, 29P, 31P 49 8789 179.4 146.1 5517R, 21P, 27P, 28P, 34P 81 6254 77.2 51.8 56 17R, 21P, 27P, 29P, 34P 405256 131.4 42.6 57 17R, 21P, 27P, 31P, 35H 181 24400 134.8 133.0 58 17R,21P, 27P, 34P, 35H 135 10340 76.6 109.4 59 14D, 17R, 21K, 27P, 35D 65918755 28.5 4.3 60 17R, 21P, 27P, 35H 215 26310 122.4 45.2 61 14H, 17R,21P, 27P, 31P 842 33403 39.7 66.7 62 14H, 17R, 21P, 27P, 31P 420 1795642.8 63.0 63 14R, 17R, 21P, 27P, 31P 3485 123900 35.6 157.1 64 14R, 17R,21P, 27P, 31P 1974 127800 64.7 126.1 65 14R, 17R, 21P, 27P, 34P 1158107934 93.2 82.4 66 14H, 17R, 21P, 27P, 35H 581 20780 35.8 45.5 67 14H,17R, 21P, 27P, 34P 172 14670 85.4 51.6 68 14H, 17R, 21P, 27P, 34P 23428486 121.9 64.4 69 14H, 17R, 21P, 27P 450 46820 104.0 65.3 70 14H, 17R,21P, 27P 355 34240 96.5 60.8 71 14G, 17R, 21P, 27P, 31P 276 44820 162.432.0 72 14A, 17R, 21P, 27P, 31P 851 220700 259.3 246.6 73 14S, 17R, 21P,27P, 31P 283 50290 177.7 51.7 74 14K, 17R, 21P, 27P, 31P 4894 10905022.3 101.0 75 14T, 17R, 21P, 27P, 31P 4025 442000 109.8 91.4 76 17R,21P, 27P, 34H 686 38935 56.8 80.0 77 17R, 21P, 27P, 34H 1496 204700136.8 118.4 78 17R, 21P, 27P, 34R 1296 90560 69.9 60.7 79 17R, 21P, 27P,34R 1652 35510 21.5 46.1 80 14H, 17R, 21P, 27P, 34H 1670 60400 36.2 68.181 14H, 17R, 21P, 27P, 34H 1424 61150 42.9 87.2 82 14R, 17R, 21P, 27P1643 142900 87.0 139.6 83 14R, 17R, 21P, 27P 2828 140500 49.7 145.6 8414H, 17R, 21P, 27P, 34R 5054 476533 94.3 119.6 85 14H, 17R, 21P, 27P,34R 3140 146100 46.5 91.8 86 17R, 21P, 27P, 34H 2802 352205 125.7 159.387 14E, 17R, 21P, 27P, 34H 2073 94463 45.6 35.6 88 14E, 17R, 21P, 27P,34R 2311 196100 84.9 46.5 89 14E, 17R, 21P, 27P, 35R 2368 115459 48.828.0 90 14H, 17R, 21P, 27P 246 18220 74.1 42.2 91 17R, 21P, 27P, 34H 38629450 76.3 100.8 92 14H, 17R, 21P, 27P 668 104500 156.4 145.0 93 14A,17R, 21P, 27P, 34H 1577 131200 83.2 101.0 94 14A, 17R, 21P, 27P, 34P 397111065 280.1 46.3 95 17R, 21P, 27P, 34R 5446 388500 71.3 63.4 96 17R,21P, 27P, 31P 529 62180 117.5 79.6 97 17R, 21P, 27P, 34H 2239 15910071.1 103.7 98 17R, 21P, 27P, 34P 137 24050 175.5 74.1 99 −1G, 1R, 14H,17R, 21P, 27P 2700 215515 79.8 100.4 100 −1G, 1R, 14H, 17R, 21P, 27P,11235 311380 27.7 65.3 34H 101 −1G, 1R, 14A, 17R, 21P, 27P, 8068 49158560.9 68.6 34H 102 −1G, 1R, 14H, 17R, 21P, 27P, 674 65880 97.7 36.2 34P103 −1G, 1R, 14A, 17R, 21P, 27P, 436 56295 129.1 26.5 34P 104 14E, 17R,21P, 27P, 34H, 35E 3136 498050 158.8 29.1 105 14E, 17R, 21P, 27P, 34R,35E 2859 452250 158.2 14.7 106 14E, 17R, 21P, 27P, 34P, 35E 182 1610688.5 17.6 107 14E, 17R, 21P, 27P, 34H, 35E 958 33100 34.6 11.1 108 14E,17R, 21P, 27P, 34R, 35E 1062 86080 81.1 28.5 109 14E, 17R, 21P, 27P,34P, 35E 164 10388 63.2 13.3 110 14E, 17R, 21P, 27P, 34P, 35R 339 38260112.9 53.6 111 17R, 21P, 27P, 34H 1237 404300 326.8 18.5 112 17R, 21P,27P, 34H 2523 706600 280.1 23.5 113 17R, 21P, 27P, 34H 1168 47040 40.359.4 114 14E, 17R, 21P, 27P, 34P, 37P 188 206 1.1 0.5 115 14H, 17R, 21P,27P, 34P, 37P 125 371 3.0 1.2 116 14H, 17R, 21P, 27P, 31P, 34P 125 905472.4 24.8 117 14E, 17R, 21P, 27P, 34P, 35R 339 15410 45.5 38.6 118 14E,17R, 21P, 27P, 34P, 35H 104 5432 52.2 21.2 119 17R, 21P, 27P, 31P, 34P,35R 381 52360 137.4 48.6 120 14S, 17R, 21P, 27P, 34P, 35E 161 139700867.7 45.3 121 14E, 17R, 21P, 31P, 34P, 35E 449 33540 74.7 22.6 122 14D,17R, 21P, 27P, 34P, 35E 324 31920 98.5 49.8 123 14D, 17R, 21P, 27P, 34P,35E 300 18590 62.0 16.7 124 14E, 17R, 21P, 27P, 34P, 35H 288 21045 73.027.3 125 14E, 17R, 21P, 27P, 34P, 35E, 152 1608 10.6 0.4 37P 126 14E,17R, 23P, 34P, 35E 659 86760 131.7 7.8 127 14E, 17R, 21P, 27P, 34P, 37F205 23360 114.0 18.0 128 14E, 17R, 21P, 27P, 35H 1157 26310 22.7 26.4129 14D, 17R, 21P, 27P, 34P, 35R 504 58470 116.0 151.1 130 14D, 17R,21P, 27P, 34P, 35R 930 222700 239.5 280.0 131 14d, 17R, 21P, 27P, 35R1692 535900 316.7 306.6 132 14D, 17R, 21P, 27P, 35R 30880 28.2

TABLE 7a rAmylin- rCTR R bind bind Ratio Ratio IC50 IC50 rCT/rAmylinhCT/hAmylin Example no. Sequence modifications (pM) (pM) binding binding1 14D, 17R, 21P, 26P, 35D 1300 135100 103.9 27.6 2 14D, 17R, 21P, 27P,35D 295 107798 365.7 47.5 3 14D, 17R, 22P, 26P, 35D 1002 16748 16.7 17.36 14E, 17R, 21P, 25P, 28P, 29P 2373 51550 21.7 20.0 7 14E, 17R, 21P, 26P1125 47250 42.0 16.5 15 14E, 17R, 21P, 27P 26.0 16 14E, 17R, 21P, 27P,35R 1210 55220 45.6 19.1 17 14E, 17R, 21P, 27P, 34H 2710 97230 35.9 12.518 14E, 17R, 21P, 27P, 35H 476 13000 27.3 9.2 19 14E, 17R, 21P, 27P 102295610 93.6 36.7 21 17R, 21P, 27P 1484 27935 18.8 24.4 22 14E, 17R, 21P,27P, 35E 2189 62460 28.5 12.3 23 17R, 21P, 27P, 35E 1120 79870 71.3 25.024 17R, 21P, 27P 3006 349700 116.3 90.0 25 17R, 21P, 27P, 35E 3485131300 37.7 56.5 26 17R, 21P, 27P, 35E 491 151700 309.2 47.5 27 17R,21P, 27P, 35E 614 90190 146.8 41.3 28 17R, 21P, 27P, 31P, 35E 1224 5489744.9 20.5 29 17R, 21P, 27P, 34P, 35E 322 21560 67.0 13.9 30 14H, 17R,21P, 27P, 35E 3143 113600 36.1 23.6 31 14E, 17R, 21P, 27P, 31P 619 2651042.8 16.0 32 14E, 17R, 21P, 27P, 34P 176 5976 34.0 10.9 33 14E, 17R,21P, 28P, 35E 2295 28885 12.6 3.9 34 17R, 21P, 27P, 35K 1715 89170 52.064.4 35 17R, 21P, 27P, 35K 948 61740 65.1 50.3 36 14E, 17R, 21P, 27P,34K 1856 60060 32.4 15.7 37 14E, 17R, 21P, 27P, 29P 514 7354 14.3 2.3 3817R, 21P, 27P, 35R 383 38020 99.2 84.9 39 17R, 21P, 27P, 34R 1770 9644054.5 29.0 40 17R, 21P, 27P, 34H 1498 69248 46.2 31.1 41 17R, 21P, 27P1371 74090 54.0 49.9 42 17R, 21P, 27P 603 15340 25.4 30.7 43 17R, 21P,27P 110 7601 69.1 34.7 44 −1K, 1R, 17R, 21P, 27P, 35H 369 19650 53.317.7 45 −1K, 1R, 17R, 21P, 27P, 35H 623 41790 67.1 26.8 46 −1G, 1R, 17R,21P, 27P 330 46780 141.8 48.9 47 −1G, 1R, 17R, 21P, 27P, 35H 203 1711084.3 44.9 48 17R, 21P, 27P 558 112300 201.3 69.7 49 17R, 21P, 27P, 31P1078 51410 47.7 10.8 50 17R, 21P, 27P, 34P 69 5634 81.7 36.0 51 14E,17R, 21P, 27P, 35R 523 61963 118.6 37.5 52 14D, 17R, 21P, 27P, 35R 335159464 476.7 81.6 53 17R, 21P, 27P, 28P, 31P 84 10930 130.1 103.5 5417R, 21P, 27P, 29P, 31P 49 8789 179.4 146.1 55 17R, 21P, 27P, 28P, 34P81 6254 77.2 51.8 56 17R, 21P, 27P, 29P, 34P 40 5256 131.4 42.6 57 17R,21P, 27P, 31P, 35H 181 24400 134.8 133.0 58 17R, 21P, 27P, 34P, 35H 13510340 76.6 109.4 59 14D, 17R, 21K, 27P, 35D 659 18755 28.5 4.3 60 17R,21P, 27P, 35H 215 26310 122.4 45.2 61 14H, 17R, 21P, 27P, 31P 842 3340339.7 66.7 62 14H, 17R, 21P, 27P, 31P 420 17956 42.8 63.0 63 14R, 17R,21P, 27P, 31P 3485 123900 35.6 157.1 64 14R, 17R, 21P, 27P, 31P 1974127800 64.7 126.1 65 14R, 17R, 21P, 27P, 34P 1158 107934 93.2 82.4 6614H, 17R, 21P, 27P, 35H 581 20780 35.8 45.5 67 14H, 17R, 21P, 27P, 34P172 14670 85.4 51.6 68 14H, 17R, 21P, 27P, 34P 234 28486 121.9 64.4 6914H, 17R, 21P, 27P 450 46820 104.0 65.3 70 14H, 17R, 21P, 27P 355 3424096.5 60.8 71 14G, 17R, 21P, 27P, 31P 276 44820 162.4 32.0 72 14A, 17R,21P, 27P, 31P 851 220700 259.3 246.6 73 14S, 17R, 21P, 27P, 31P 28350290 177.7 51.7 74 14K, 17R, 21P, 27P, 31P 4894 109050 22.3 101.0 7514T, 17R, 21P, 27P, 31P 4025 442000 109.8 91.4 76 17R, 21P, 27P, 34H 68638935 56.8 80.0 77 17R, 21P, 27P, 34H 1496 204700 136.8 118.4 78 17R,21P, 27P, 34R 1296 90560 69.9 60.7 79 17R, 21P, 27P, 34R 1652 35510 21.546.1 80 14H, 17R, 21P, 27P, 34H 1670 60400 36.2 68.1 81 14H, 17R, 21P,27P, 34H 1424 61150 42.9 87.2 82 14R, 17R, 21P, 27P 1643 142900 87.0139.6 83 14R, 17R, 21P, 27P 2828 140500 49.7 145.6 84 14H, 17R, 21P,27P, 34R 5054 476533 94.3 119.6 85 14H, 17R, 21P, 27P, 34R 3140 14610046.5 91.8 86 17R, 21P, 27P, 34H 2802 352205 125.7 159.3 87 14E, 17R,21P, 27P, 34H 2073 94463 45.6 35.6 88 14E, 17R, 21P, 27P, 34R 2311196100 84.9 46.5 89 14E, 17R, 21P, 27P, 35R 2368 115459 48.8 28.0 9014H, 17R, 21P, 27P 246 18220 74.1 42.2 91 17R, 21P, 27P, 34H 386 2945076.3 100.8 92 14H, 17R, 21P, 27P 668 104500 156.4 145.0 93 14A, 17R,21P, 27P, 34H 1577 131200 83.2 101.0 94 14A, 17R, 21P, 27P, 34P 397111065 280.1 46.3 95 17R, 21P, 27P, 34R 5446 388500 71.3 63.4 96 17R,21P, 27P, 31P 529 62180 117.5 79.6 97 17R, 21P, 27P, 34H 2239 15910071.1 103.7 98 17R, 21P, 27P, 34P 137 24050 175.5 74.1 99 −1G, 1R, 14H,17R, 21P, 27P 2700 215515 79.8 100.4 100 −1G, 1R, 14H, 17R, 21P, 27P,11235 311380 27.7 65.3 34H 101 −1G, 1R, 14A, 17R, 21P, 27P, 8068 49158560.9 68.6 34H 102 −1G, 1R, 14H, 17R, 21P, 27P, 674 65880 97.7 36.2 34P103 −1G, 1R, 14A, 17R, 21P, 27P, 436 56295 129.1 26.5 34P 104 14E, 17R,21P, 27P, 34H, 35E 3136 498050 158.8 29.1 105 14E, 17R, 21P, 27P, 34R,35E 2859 452250 158.2 14.7 106 14E, 17R, 21P, 27P, 34P, 35E 182 1610688.5 17.6 107 14E, 17R, 21P, 27P, 34H, 35E 958 33100 34.6 11.1 108 14E,17R, 21P, 27P, 34R, 35E 1062 86080 81.1 28.5 109 14E, 17R, 21P, 27P,34P, 35E 164 10388 63.2 13.3 110 14E, 17R, 21P, 27P, 34P, 35R 339 38260112.9 53.6 111 17R, 21P, 27P, 34H 1237 404300 326.8 18.5 112 17R, 21P,27P, 34H 2523 706600 280.1 23.5 113 17R, 21P, 27P, 34H 1168 47040 40.359.4 116 14H, 17R, 21P, 27P, 31P, 34P 125 9054 72.4 24.8 117 14E, 17R,21P, 27P, 34P, 35R 339 15410 45.5 38.6 118 14E, 17R, 21P, 27P, 34P, 35H104 5432 52.2 21.2 119 17R, 21P, 27P, 31P, 34P, 35R 381 52360 137.4 48.6120 14S, 17R, 21P, 27P, 34P, 35E 161 139700 867.7 45.3 121 14E, 17R,21P, 31P, 34P, 35E 449 33540 74.7 22.6 122 14D, 17R, 21P, 27P, 34P, 35E324 31920 98.5 49.8 123 14D, 17R, 21P, 27P, 34P, 35E 300 18590 62.0 16.7124 14E, 17R, 21P, 27P, 34P, 35H 288 21045 73.0 27.3 125 14E, 17R, 21P,27P, 34P, 35E, 152 1608 10.6 0.4 37P 126 14E, 17R, 23P, 34P, 35E 65986760 131.7 7.8 127 14E, 17R, 21P, 27P, 34P, 37F 205 23360 114.0 18.0128 14E, 17R, 21P, 27P, 35H 1157 26310 22.7 26.4 129 14D, 17R, 21P, 27P,34P, 35R 504 58470 116.0 151.1 130 14D, 17R, 21P, 27P, 34P, 35R 930222700 239.5 280.0 131 14d, 17R, 21P, 27P, 35R 1692 535900 316.7 306.6132 14D, 17R, 21P, 27P, 35R 30880 28.2

TABLE 7b rAmylin- rCTR R bind bind Ratio Ratio IC50 IC50 rCT/rAmylinhCT/hAmylin Example no. Sequence modifications (pM) (pM) binding binding1 14D, 17R, 21P, 26P, 35D 1300 135100 103.9 27.6 2 14D, 17R, 21P, 27P,35D 295 107798 365.7 47.5 3 14D, 17R, 22P, 26P, 35D 1002 16748 16.7 17.36 14E, 17R, 21P, 25P, 28P, 29P 2373 51550 21.7 20.0 7 14E, 17R, 21P, 26P1125 47250 42.0 16.5 15 14E, 17R, 21P, 27P 26.0 16 14E, 17R, 21P, 27P,35R 1210 55220 45.6 19.1 17 14E, 17R, 21P, 27P, 34H 2710 97230 35.9 12.519 14E, 17R, 21P, 27P 1022 95610 93.6 36.7 21 17R, 21P, 27P 1484 2793518.8 24.4 22 14E, 17R, 21P, 27P, 35E 2189 62460 28.5 12.3 23 17R, 21P,27P, 35E 1120 79870 71.3 25.0 24 17R, 21P, 27P 3006 349700 116.3 90.0 2517R, 21P, 27P, 35E 3485 131300 37.7 56.5 26 17R, 21P, 27P, 35E 491151700 309.2 47.5 27 17R, 21P, 27P, 35E 614 90190 146.8 41.3 28 17R,21P, 27P, 31P, 35E 1224 54897 44.9 20.5 29 17R, 21P, 27P, 34P, 35E 32221560 67.0 13.9 30 14H, 17R, 21P, 27P, 35E 3143 113600 36.1 23.6 31 14E,17R, 21P, 27P, 31P 619 26510 42.8 16.0 32 14E, 17R, 21P, 27P, 34P 1765976 34.0 10.9 34 17R, 21P, 27P, 35K 1715 89170 52.0 64.4 35 17R, 21P,27P, 35K 948 61740 65.1 50.3 36 14E, 17R, 21P, 27P, 34K 1856 60060 32.415.7 38 17R, 21P, 27P, 35R 383 38020 99.2 84.9 39 17R, 21P, 27P, 34R1770 96440 54.5 29.0 40 17R, 21P, 27P, 34H 1498 69248 46.2 31.1 41 17R,21P, 27P 1371 74090 54.0 49.9 42 17R, 21P, 27P 603 15340 25.4 30.7 4317R, 21P, 27P 110 7601 69.1 34.7 44 −1K, 1R, 17R, 21P, 27P, 35H 36919650 53.3 17.7 45 −1K, 1R, 17R, 21P, 27P, 35H 623 41790 67.1 26.8 46−1G, 1R, 17R, 21P, 27P 330 46780 141.8 48.9 47 −1G, 1R, 17R, 21P, 27P,35H 203 17110 84.3 44.9 48 17R, 21P, 27P 558 112300 201.3 69.7 49 17R,21P, 27P, 31P 1078 51410 47.7 10.8 50 17R, 21P, 27P, 34P 69 5634 81.736.0 51 14E, 17R, 21P, 27P, 35R 523 61963 118.6 37.5 52 14D, 17R, 21P,27P, 35R 335 159464 476.7 81.6 53 17R, 21P, 27P, 28P, 31P 84 10930 130.1103.5 54 17R, 21P, 27P, 29P, 31P 49 8789 179.4 146.1 55 17R, 21P, 27P,28P, 34P 81 6254 77.2 51.8 56 17R, 21P, 27P, 29P, 34P 40 5256 131.4 42.657 17R, 21P, 27P, 31P, 35H 181 24400 134.8 133.0 58 17R, 21P, 27P, 34P,35H 135 10340 76.6 109.4 60 17R, 21P, 27P, 35H 215 26310 122.4 45.2 6114H, 17R, 21P, 27P, 31P 842 33403 39.7 66.7 62 14H, 17R, 21P, 27P, 31P420 17956 42.8 63.0 63 14R, 17R, 21P, 27P, 31P 3485 123900 35.6 157.1 6414R, 17R, 21P, 27P, 31P 1974 127800 64.7 126.1 65 14R, 17R, 21P, 27P,34P 1158 107934 93.2 82.4 66 14H, 17R, 21P, 27P, 35H 581 20780 35.8 45.567 14H, 17R, 21P, 27P, 34P 172 14670 85.4 51.6 68 14H, 17R, 21P, 27P,34P 234 28486 121.9 64.4 69 14H, 17R, 21P, 27P 450 46820 104.0 65.3 7014H, 17R, 21P, 27P 355 34240 96.5 60.8 71 14G, 17R, 21P, 27P, 31P 27644820 162.4 32.0 72 14A, 17R, 21P, 27P, 31P 851 220700 259.3 246.6 7314S, 17R, 21P, 27P, 31P 283 50290 177.7 51.7 74 14K, 17R, 21P, 27P, 31P4894 109050 22.3 101.0 75 14T, 17R, 21P, 27P, 31P 4025 442000 109.8 91.476 17R, 21P, 27P, 34H 686 38935 56.8 80.0 77 17R, 21P, 27P, 34H 1496204700 136.8 118.4 78 17R, 21P, 27P, 34R 1296 90560 69.9 60.7 79 17R,21P, 27P, 34R 1652 35510 21.5 46.1 80 14H, 17R, 21P, 27P, 34H 1670 6040036.2 68.1 81 14H, 17R, 21P, 27P, 34H 1424 61150 42.9 87.2 82 14R, 17R,21P, 27P 1643 142900 87.0 139.6 83 14R, 17R, 21P, 27P 2828 140500 49.7145.6 84 14H, 17R, 21P, 27P, 34R 5054 476533 94.3 119.6 85 14H, 17R,21P, 27P, 34R 3140 146100 46.5 91.8 86 17R, 21P, 27P, 34H 2802 352205125.7 159.3 87 14E, 17R, 21P, 27P, 34H 2073 94463 45.6 35.6 88 14E, 17R,21P, 27P, 34R 2311 196100 84.9 46.5 89 14E, 17R, 21P, 27P, 35R 2368115459 48.8 28.0 90 14H, 17R, 21P, 27P 246 18220 74.1 42.2 91 17R, 21P,27P, 34H 386 29450 76.3 100.8 92 14H, 17R, 21P, 27P 668 104500 156.4145.0 93 14A, 17R, 21P, 27P, 34H 1577 131200 83.2 101.0 94 14A, 17R,21P, 27P, 34P 397 111065 280.1 46.3 95 17R, 21P, 27P, 34R 5446 38850071.3 63.4 96 17R, 21P, 27P, 31P 529 62180 117.5 79.6 97 17R, 21P, 27P,34H 2239 159100 71.1 103.7 98 17R, 21P, 27P, 34P 137 24050 175.5 74.1 99−1G, 1R, 14H, 17R, 21P, 27P 2700 215515 79.8 100.4 100 −1G, 1R, 14H,17R, 21P, 27P, 11235 311380 27.7 65.3 34H 101 −1G, 1R, 14A, 17R, 21P,27P, 8068 491585 60.9 68.6 34H 102 −1G, 1R, 14H, 17R, 21P, 27P, 67465880 97.7 36.2 34P 103 −1G, 1R, 14A, 17R, 21P, 27P, 436 56295 129.126.5 34P 104 14E, 17R, 21P, 27P, 34H, 35E 3136 498050 158.8 29.1 10514E, 17R, 21P, 27P, 34R, 35E 2859 452250 158.2 14.7 106 14E, 17R, 21P,27P, 34P, 35E 182 16106 88.5 17.6 107 14E, 17R, 21P, 27P, 34H, 35E 95833100 34.6 11.1 108 14E, 17R, 21P, 27P, 34R, 35E 1062 86080 81.1 28.5109 14E, 17R, 21P, 27P, 34P, 35E 164 10388 63.2 13.3 110 14E, 17R, 21P,27P, 34P, 35R 339 38260 112.9 53.6 111 17R, 21P, 27P, 34H 1237 404300326.8 18.5 112 17R, 21P, 27P, 34H 2523 706600 280.1 23.5 113 17R, 21P,27P, 34H 1168 47040 40.3 59.4 116 14H, 17R, 21P, 27P, 31P, 34P 125 905472.4 24.8 117 14E, 17R, 21P, 27P, 34P, 35R 339 15410 45.5 38.6 118 14E,17R, 21P, 27P, 34P, 35H 104 5432 52.2 21.2 119 17R, 21P, 27P, 31P, 34P,35R 381 52360 137.4 48.6 120 14S, 17R, 21P, 27P, 34P, 35E 161 139700867.7 45.3 121 14E, 17R, 21P, 31P, 34P, 35E 449 33540 74.7 22.6 122 14D,17R, 21P, 27P, 34P, 35E 324 31920 98.5 49.8 123 14D, 17R, 21P, 27P, 34P,35E 300 18590 62.0 16.7 124 14E, 17R, 21P, 27P, 34P, 35H 288 21045 73.027.3 127 14E, 17R, 21P, 27P, 34P, 37F 205 23360 114.0 18.0 128 14E, 17R,21P, 27P, 35H 1157 26310 22.7 26.4 129 14D, 17R, 21P, 27P, 34P, 35R 50458470 116.0 151.1 130 14D, 17R, 21P, 27P, 34P, 35R 930 222700 239.5280.0 131 14d, 17R, 21P, 27P, 35R 1692 535900 316.7 306.6 132 14D, 17R,21P, 27P, 35R 30880 28.2

TABLE 7c rAmylin- rCTR R bind bind Ratio Ratio IC50 IC50 rCT/rAmylinhCT/hAmylin Example no. Sequence modifications (pM) (pM) binding binding1 14D, 17R, 21P, 26P, 35D 1300 135100 103.9 27.6 2 14D, 17R, 21P, 27P,35D 295 107798 365.7 47.5 6 14E, 17R, 21P, 25P, 28P, 29P 2373 51550 21.720.0 15 14E, 17R, 21P, 27P 26.0 19 14E, 17R, 21P, 27P 1022 95610 93.636.7 21 17R, 21P, 27P 1484 27935 18.8 24.4 22 14E, 17R, 21P, 27P, 35E2189 62460 28.5 12.3 23 17R, 21P, 27P, 35E 1120 79870 71.3 25.0 24 17R,21P, 27P 3006 349700 116.3 90.0 25 17R, 21P, 27P, 35E 3485 131300 37.756.5 26 17R, 21P, 27P, 35E 491 151700 309.2 47.5 27 17R, 21P, 27P, 35E614 90190 146.8 41.3 28 17R, 21P, 27P, 31P, 35E 1224 54897 44.9 20.5 3014H, 17R, 21P, 27P, 35E 3143 113600 36.1 23.6 34 17R, 21P, 27P, 35K 171589170 52.0 64.4 35 17R, 21P, 27P, 35K 948 61740 65.1 50.3 36 14E, 17R,21P, 27P, 34K 1856 60060 32.4 15.7 38 17R, 21P, 27P, 35R 383 38020 99.284.9 39 17R, 21P, 27P, 34R 1770 96440 54.5 29.0 40 17R, 21P, 27P, 34H1498 69248 46.2 31.1 41 17R, 21P, 27P 1371 74090 54.0 49.9 42 17R, 21P,27P 603 15340 25.4 30.7 43 17R, 21P, 27P 110 7601 69.1 34.7 45 −1K, 1R,17R, 21P, 27P, 35H 623 41790 67.1 26.8 46 −1G, 1R, 17R, 21P, 27P 33046780 141.8 48.9 47 −1G, 1R, 17R, 21P, 27P, 35H 203 17110 84.3 44.9 4817R, 21P, 27P 558 112300 201.3 69.7 50 17R, 21P, 27P, 34P 69 5634 81.736.0 51 14E, 17R, 21P, 27P, 35R 523 61963 118.6 37.5 52 14D, 17R, 21P,27P, 35R 335 159464 476.7 81.6 53 17R, 21P, 27P, 28P, 31P 84 10930 130.1103.5 54 17R, 21P, 27P, 29P, 31P 49 8789 179.4 146.1 55 17R, 21P, 27P,28P, 34P 81 6254 77.2 51.8 56 17R, 21P, 27P, 29P, 34P 40 5256 131.4 42.657 17R, 21P, 27P, 31P, 35H 181 24400 134.8 133.0 58 17R, 21P, 27P, 34P,35H 135 10340 76.6 109.4 60 17R, 21P, 27P, 35H 215 26310 122.4 45.2 6114H, 17R, 21P, 27P, 31P 842 33403 39.7 66.7 62 14H, 17R, 21P, 27P, 31P420 17956 42.8 63.0 63 14R, 17R, 21P, 27P, 31P 3485 123900 35.6 157.1 6414R, 17R, 21P, 27P, 31P 1974 127800 64.7 126.1 65 14R, 17R, 21P, 27P,34P 1158 107934 93.2 82.4 66 14H, 17R, 21P, 27P, 35H 581 20780 35.8 45.567 14H, 17R, 21P, 27P, 34P 172 14670 85.4 51.6 68 14H, 17R, 21P, 27P,34P 234 28486 121.9 64.4 69 14H, 17R, 21P, 27P 450 46820 104.0 65.3 7014H, 17R, 21P, 27P 355 34240 96.5 60.8 71 14G, 17R, 21P, 27P, 31P 27644820 162.4 32.0 72 14A, 17R, 21P, 27P, 31P 851 220700 259.3 246.6 7314S, 17R, 21P, 27P, 31P 283 50290 177.7 51.7 74 14K, 17R, 21P, 27P, 31P4894 109050 22.3 101.0 75 14T, 17R, 21P, 27P, 31P 4025 442000 109.8 91.476 17R, 21P, 27P, 34H 686 38935 56.8 80.0 77 17R, 21P, 27P, 34H 1496204700 136.8 118.4 78 17R, 21P, 27P, 34R 1296 90560 69.9 60.7 79 17R,21P, 27P, 34R 1652 35510 21.5 46.1 80 14H, 17R, 21P, 27P, 34H 1670 6040036.2 68.1 81 14H, 17R, 21P, 27P, 34H 1424 61150 42.9 87.2 82 14R, 17R,21P, 27P 1643 142900 87.0 139.6 83 14R, 17R, 21P, 27P 2828 140500 49.7145.6 84 14H, 17R, 21P, 27P, 34R 5054 476533 94.3 119.6 85 14H, 17R,21P, 27P, 34R 3140 146100 46.5 91.8 86 17R, 21P, 27P, 34H 2802 352205125.7 159.3 87 14E, 17R, 21P, 27P, 34H 2073 94463 45.6 35.6 88 14E, 17R,21P, 27P, 34R 2311 196100 84.9 46.5 89 14E, 17R, 21P, 27P, 35R 2368115459 48.8 28.0 90 14H, 17R, 21P, 27P 246 18220 74.1 42.2 91 17R, 21P,27P, 34H 386 29450 76.3 100.8 92 14H, 17R, 21P, 27P 668 104500 156.4145.0 93 14A, 17R, 21P, 27P, 34H 1577 131200 83.2 101.0 94 14A, 17R,21P, 27P, 34P 397 111065 280.1 46.3 95 17R, 21P, 27P, 34R 5446 38850071.3 63.4 96 17R, 21P, 27P, 31P 529 62180 117.5 79.6 97 17R, 21P, 27P,34H 2239 159100 71.1 103.7 98 17R, 21P, 27P, 34P 137 24050 175.5 74.1 99−1G, 1R, 14H, 17R, 21P, 27P 2700 215515 79.8 100.4 100 −1G, 1R, 14H,17R, 21P, 27P, 11235 311380 27.7 65.3 34H 101 −1G, 1R, 14A, 17R, 21P,27P, 8068 491585 60.9 68.6 34H 102 −1G, 1R, 14H, 17R, 21P, 27P, 67465880 97.7 36.2 34P 103 −1G, 1R, 14A, 17R, 21P, 27P, 436 56295 129.126.5 34P 104 14E, 17R, 21P, 27P, 34H, 35E 3136 498050 158.8 29.1 10814E, 17R, 21P, 27P, 34R, 35E 1062 86080 81.1 28.5 110 14E, 17R, 21P,27P, 34P, 35R 339 38260 112.9 53.6 112 17R, 21P, 27P, 34H 2523 706600280.1 23.5 113 17R, 21P, 27P, 34H 1168 47040 40.3 59.4 116 14H, 17R,21P, 27P, 31P, 34P 125 9054 72.4 24.8 117 14E, 17R, 21P, 27P, 34P, 35R339 15410 45.5 38.6 118 14E, 17R, 21P, 27P, 34P, 35H 104 5432 52.2 21.2119 17R, 21P, 27P, 31P, 34P, 35R 381 52360 137.4 48.6 120 14S, 17R, 21P,27P, 34P, 35E 161 139700 867.7 45.3 121 14E, 17R, 21P, 31P, 34P, 35E 44933540 74.7 22.6 122 14D, 17R, 21P, 27P, 34P, 35E 324 31920 98.5 49.8 12414E, 17R, 21P, 27P, 34P, 35H 288 21045 73.0 27.3 128 14E, 17R, 21P, 27P,35H 1157 26310 22.7 26.4 129 14D, 17R, 21P, 27P, 34P, 35R 504 58470116.0 151.1 130 14D, 17R, 21P, 27P, 34P, 35R 930 222700 239.5 280.0 13114d, 17R, 21P, 27P, 35R 1692 535900 316.7 306.6 132 14D, 17R, 21P, 27P,35R 30880 28.2

Solubility

The solubility of the polypeptides was tested as described in assay (IV)and results shown in Table 8 and in Table 9.

The compounds disclosed in Table 8 and Table 9 have a hAmylinR IC50value of less than 1200 pM. Details of the albumin binding moiety,linker and acylation sites have been removed from these Tables. For fullstructural information please consult the entry with a correspondingcompound number in Table 2. Further details regarding the compounds,such as IUPAC nomenclature may be found in Table 14.

TABLE 8 Solubility Solubility pH pH 4.0 Solubility pH Solubility pH 3.0Concen- 5.0 6.0 Example Concentration tration ConcentrationConcentration no. (μM) (μM) (μM) (μM) 1 ≧200 ≧200 172 ≧200 2 ≧200 ≧200≧200 ≧200 3 ≧200 96 141 189 4 5 6 7 8 ≧200 ≧200 ≧200 ≧200 9 ≧200 ≧200≧200 ≧200 10 ≧200 ≧200 ≧200 ≧200 11 ≧200 ≧200 ≧200 ≧200 12 ≧200 ≧200≧200 ≧200 13 14 ≧200 ≧200 ≧200 ≧200 15 ≧200 ≧200 ≧200 ≧200 16 ≧200 ≧200≧200 ≧200 17 ≧200 ≧200 ≧200 ≧200 18 ≧200 ≧200 ≧200 ≧200 19 ≧200 ≧200≧200 ≧200 20 ≧200 ≧200 ≧200 ≧200 21 ≧200 ≧200 ≧200 ≧200 22 ≧200 ≧200≧200 195 23 ≧200 ≧200 ≧200 ≧200 24 ≧200 ≧200 ≧200 ≧200 25 ≧200 ≧200 ≧200≧200 26 ≧200 ≧200 ≧200 ≧200 27 ≧200 ≧200 ≧200 ≧200 28 ≧200 ≧200 ≧200≧200 29 ≧200 ≧200 ≧200 ≧200 30 ≧200 ≧200 ≧200 ≧200 31 ≧200 ≧200 ≧200≧200 32 ≧200 ≧200 ≧200 ≧200 33 ≧200 ≧200 ≧200 ≧200 34 ≧200 ≧200 ≧200≧200 35 ≧200 ≧200 ≧200 ≧200 36 ≧200 ≧200 ≧200 ≧200 37 ≧200 ≧200 ≧200≧200 38 ≧200 ≧200 ≧200 ≧200 39 ≧200 ≧200 ≧200 ≧200 40 ≧200 ≧200 ≧200≧200 41 42 ≧200 ≧200 ≧200 ≧200 43 ≧200 ≧200 ≧200 ≧200 44 ≧200 ≧200 ≧200≧200 45 ≧200 ≧200 ≧200 ≧200 46 ≧200 ≧200 ≧200 ≧200 47 ≧200 ≧200 ≧200≧200 48 ≧200 ≧200 ≧200 ≧200 49 ≧200 ≧200 ≧200 ≧200 50 ≧200 ≧200 ≧200≧200 51 ≧200 ≧200 ≧200 ≧200 52 ≧200 ≧200 ≧200 ≧200 53 ≧200 ≧200 ≧200≧200 54 ≧200 ≧200 ≧200 ≧200 55 ≧200 ≧200 ≧200 ≧200 56 ≧200 ≧200 ≧200≧200 57 ≧200 ≧200 ≧200 ≧200 58 ≧200 ≧200 ≧200 ≧200 59 ≧200 ≧200 ≧200≧200 60 ≧200 ≧200 ≧200 ≧200 61 ≧200 ≧200 ≧200 ≧200 62 ≧200 ≧200 ≧200≧200 63 ≧200 ≧200 ≧200 ≧200 64 ≧200 ≧200 ≧200 ≧200 65 ≧200 ≧200 ≧200≧200 66 ≧200 ≧200 ≧200 ≧200 67 ≧200 ≧200 ≧200 ≧200 68 ≧200 ≧200 ≧200≧200 69 ≧200 ≧200 ≧200 ≧200 70 ≧200 ≧200 ≧200 ≧200 71 ≧200 ≧200 ≧200≧200 72 ≧200 ≧200 ≧200 ≧200 73 ≧200 ≧200 ≧200 ≧200 74 ≧200 ≧200 ≧200≧200 75 ≧200 ≧200 ≧200 ≧200 76 ≧200 ≧200 ≧200 ≧200 77 ≧200 ≧200 ≧200≧200 78 ≧200 ≧200 ≧200 ≧200 79 ≧200 ≧200 ≧200 ≧200 80 ≧200 ≧200 ≧200≧200 81 ≧200 ≧200 ≧200 ≧200 82 ≧200 ≧200 ≧200 ≧200 83 ≧200 ≧200 ≧200≧200 84 ≧200 ≧200 ≧200 ≧200 85 ≧200 ≧200 ≧200 ≧200 86 ≧200 ≧200 ≧200≧200 87 ≧200 ≧200 ≧200 156 88 ≧200 ≧200 ≧200 ≧200 89 ≧200 ≧200 ≧200 ≧20090 ≧200 ≧200 ≧200 ≧200 91 ≧200 ≧200 ≧200 ≧200 92 ≧200 ≧200 ≧200 ≧200 93≧200 ≧200 ≧200 ≧200 94 ≧200 ≧200 ≧200 ≧200 95 ≧200 ≧200 ≧200 ≧200 96≧200 ≧200 ≧200 ≧200 97 ≧200 ≧200 ≧200 ≧200 98 ≧200 ≧200 ≧200 ≧200 99≧200 ≧200 ≧200 ≧200 100 ≧200 ≧200 ≧200 101 ≧200 ≧200 ≧200 ≧200 102 ≧200197 195 ≧200 103 ≧200 ≧200 ≧200 ≧200 104 ≧200 ≧200 ≧200 ≧200 105 ≧200≧200 ≧200 ≧200 106 ≧200 ≧200 ≧200 ≧200 107 ≧200 ≧200 ≧200 ≧200 108 ≧200≧200 ≧200 ≧200 109 ≧200 ≧200 ≧200 ≧200 110 ≧200 ≧200 ≧200 ≧200 111 ≧200≧200 ≧200 ≧200 112 ≧200 ≧200 ≧200 ≧200 113 ≧200 ≧200 ≧200 ≧200 114 ≧200≧200 ≧200 ≧200 115 ≧200 ≧200 ≧200 ≧200 116 ≧200 ≧200 ≧200 ≧200 117 ≧200≧200 ≧200 ≧200 118 ≧200 ≧200 ≧200 ≧200 119 174 ≧200 ≧200 ≧200 120 ≧200≧200 ≧200 ≧200 121 ≧200 ≧200 ≧200 122 ≧200 ≧200 ≧200 ≧200 123 ≧200 ≧200≧200 ≧200 124 ≧200 ≧200 ≧200 ≧200 125 ≧200 ≧200 ≧200 ≧200 126 7 0 64 127128 ≧200 ≧200 ≧200 ≧200 129 ≧200 ≧200 ≧200 ≧200 130 ≧200 ≧200 ≧200 ≧200131 132 ≧200 ≧200 ≧200 ≧200

TABLE 8a Solubility Solubility pH pH 4.0 Solubility pH Solubility pH 3.0Concen- 5.0 6.0 Example Concentration tration ConcentrationConcentration no. (μM) (μM) (μM) (μM) 126 7 0 64

TABLE 9 Solubility Solubility pH pH 7.0 Solubility pH Solubility pH 6.5Concen- 7.5 8.0 Example Concentration tration ConcentrationConcentration no. (μM) (μM) (μM) (μM) 1 ≧200 ≧200 ≧200 ≧200 2 190 ≧200≧200 ≧200 3 ≧200 195 ≧200 ≧200 4 5 6 7 8 ≧200 ≧200 ≧200 ≧200 9 ≧200 ≧200≧200 ≧200 10 ≧200 ≧200 ≧200 ≧200 11 ≧200 ≧200 ≧200 ≧200 12 ≧200 ≧200≧200 ≧200 13 14 ≧200 ≧200 ≧200 ≧200 15 ≧200 ≧200 ≧200 ≧200 16 ≧200 ≧200≧200 ≧200 17 ≧200 ≧200 159 154 18 ≧200 177 122 111 19 ≧200 ≧200 ≧200≧200 20 ≧200 ≧200 ≧200 ≧200 21 ≧200 ≧200 ≧200 195 22 ≧200 ≧200 ≧200 ≧20023 ≧200 ≧200 ≧200 ≧200 24 ≧200 ≧200 ≧200 ≧200 25 ≧200 ≧200 ≧200 ≧200 26≧200 ≧200 ≧200 ≧200 27 ≧200 ≧200 ≧200 ≧200 28 ≧200 ≧200 ≧200 ≧200 29≧200 ≧200 ≧200 ≧200 30 ≧200 ≧200 ≧200 ≧200 31 ≧200 ≧200 ≧200 ≧200 32≧200 ≧200 ≧200 ≧200 33 ≧200 ≧200 ≧200 ≧200 34 ≧200 ≧200 ≧200 ≧200 35≧200 ≧200 ≧200 ≧200 36 ≧200 ≧200 ≧200 ≧200 37 ≧200 ≧200 ≧200 ≧200 38≧200 ≧200 ≧200 ≧200 39 ≧200 ≧200 ≧200 ≧200 40 ≧200 ≧200 ≧200 ≧200 41 42≧200 163 84 65 43 ≧200 ≧200 ≧200 ≧200 44 ≧200 ≧200 87 39 45 ≧200 ≧200≧200 110 46 ≧200 186 106 145 47 ≧200 ≧200 50 68 48 ≧200 ≧200 ≧200 ≧20049 ≧200 ≧200 ≧200 ≧200 50 ≧200 ≧200 ≧200 ≧200 51 ≧200 ≧200 183 109 52≧200 155 106 110 53 ≧200 ≧200 ≧200 ≧200 54 ≧200 ≧200 ≧200 ≧200 55 ≧200≧200 ≧200 119 56 ≧200 ≧200 ≧200 147 57 ≧200 ≧200 142 101 58 ≧200 ≧200 9648 59 ≧200 ≧200 ≧200 ≧200 60 ≧200 ≧200 186 98 61 ≧200 ≧200 ≧200 153 62≧200 ≧200 ≧200 189 63 ≧200 ≧200 ≧200 ≧200 64 ≧200 ≧200 ≧200 ≧200 65 ≧200≧200 ≧200 ≧200 66 ≧200 ≧200 131 52 67 ≧200 ≧200 ≧200 178 68 ≧200 ≧200193 138.5 69 ≧200 ≧200 ≧200 ≧200 70 ≧200 ≧200 ≧200 ≧200 71 ≧200 ≧200≧200 ≧200 72 ≧200 ≧200 ≧200 194 73 ≧200 ≧200 ≧200 172 74 ≧200 ≧200 ≧200≧200 75 ≧200 ≧200 193 150 76 ≧200 ≧200 ≧200 139.5 77 ≧200 ≧200 147 59 78≧200 ≧200 ≧200 ≧200 79 ≧200 ≧200 ≧200 ≧200 80 ≧200 ≧200 ≧200 ≧200 81≧200 ≧200 ≧200 ≧200 82 ≧200 ≧200 ≧200 ≧200 83 ≧200 ≧200 ≧200 ≧200 84≧200 ≧200 ≧200 ≧200 85 ≧200 ≧200 ≧200 ≧200 86 ≧200 ≧200 157 ≧200 87 144146 ≧200 ≧200 88 ≧200 162 113 108 89 ≧200 172 161.5 149 90 ≧200 ≧200≧200 ≧200 91 ≧200 ≧200 ≧200 ≧200 92 ≧200 ≧200 ≧200 ≧200 93 ≧200 ≧200≧200 ≧200 94 ≧200 ≧200 ≧200 ≧200 95 ≧200 ≧200 ≧200 ≧200 96 ≧200 ≧200≧200 ≧200 97 ≧200 ≧200 88 43 98 ≧200 ≧200 ≧200 176 99 ≧200 154 94 120100 ≧200 109 26 31 101 ≧200 182 69 83 102 ≧200 154 88 113 103 ≧200 ≧200141 194 104 ≧200 ≧200 ≧200 ≧200 105 ≧200 ≧200 ≧200 ≧200 106 ≧200 ≧200≧200 ≧200 107 ≧200 ≧200 ≧200 ≧200 108 ≧200 ≧200 ≧200 ≧200 109 ≧200 ≧200≧200 ≧200 110 ≧200 ≧200 184 166 111 ≧200 ≧200 ≧200 165 112 ≧200 ≧200≧200 ≧200 113 ≧200 154 96 114 ≧200 ≧200 ≧200 ≧200 115 ≧200 ≧200 ≧200≧200 116 ≧200 ≧200 ≧200 180 117 ≧200 ≧200 ≧200 147 118 ≧200 ≧200 ≧200≧200 119 174 182 112 32 120 ≧200 ≧200 ≧200 ≧200 121 ≧200 ≧200 ≧200 ≧200122 ≧200 ≧200 ≧200 ≧200 123 ≧200 ≧200 ≧200 ≧200 124 ≧200 ≧200 ≧200 165125 ≧200 ≧200 ≧200 ≧200 126 131 198 ≧200 127 128 ≧200 ≧200 ≧200 ≧200 129≧200 ≧200 187 102 130 ≧200 ≧200 ≧200 ≧200 131 132 ≧200 ≧200 ≧200 ≧200

TABLE 9a Solubility pH 6.5 Solubility pH Solubility pH Solubility pHConcen- 7.0 7.5 8.0 Example tration Concentration ConcentrationConcentration no. (μM) (μM) (μM) (μM) 58 ≧200 ≧200 96 48 66 ≧200 ≧200131 52 77 ≧200 ≧200 147 59 97 ≧200 ≧200 88 43 100 ≧200 109 26 31 119 174182 112 32

Physical Stability

The polypeptides were tested for physical stability in the ThT assay(Assay (III)) and the data is presented in Table 10.

The compounds disclosed in Table 10 have a hAmylinR IC50 value of lessthan 1200 pM. Details of the albumin binding moiety, linker andacylation sites have been removed from these Tables. For full structuralinformation please consult the entry with a corresponding compoundnumber in Table 2. Further details regarding the compounds, such asIUPAC nomenclature may be found in Table 14.

TABLE 10 ThT pH 4.0 ThT pH 4.0 recovery Example no. Sequencemodifications pI lag time (h) (%) 1 14D, 17R, 21P, 26P, 35D 4.8 0 0 214D, 17R, 21P, 27P, 35D 4.8 10 1 3 14D, 17R, 22P, 26P, 35D 4.8 4 14E,17R, 21P, 25P, 28P, 29P, 37P 8.6 5 14E, 17R, 21P, 26P, 37P 8.6 6 14E,17R, 21P, 25P, 28P, 29P 8.2 7 14E, 17R, 21P, 26P 8.2 8 14E, 17R, 21P,27P, 37P 8.6 45 94 9 14E, 17R, 21P, 27P 8.2 19 51 10 14D, 17R, 21P, 27P,37P 8.6 45 91 11 14E, 17R, 21P, 27P, 35D, 37P 5.9 45 89 12 14E, 17R,21P, 27P, 37P 7.2 45 83 13 14E, 17R, 21P, 27P, 37P 5.8 45 75 14 14E,17R, 21P, 27P, 37P 5.9 45 88 15 14E, 17R, 21P, 27P 5.9 45 20 16 14E,17R, 21P, 27P, 35R 10.1 45 89 17 14E, 17R, 21P, 27P, 34H 8.4 45 92 1814E, 17R, 21P, 27P, 35H 8.4 45 100 19 14E, 17R, 21P, 27P 8.2 9 0 20 14E,17R, 21P, 27P, 37P 8.6 45 88 21 17R, 21P, 27P 10.1 24 75 22 14E, 17R,21P, 27P, 35E 5.9 45 89 23 17R, 21P, 27P, 35E 8.2 3 0 24 17R, 21P, 27P10.1 34 0 25 17R, 21P, 27P, 35E 7.2 2 0 26 17R, 21P, 27P, 35E 7.2 12 027 17R, 21P, 27P, 35E 7.2 28 3 28 17R, 21P, 27P, 31P, 35E 8.2 40 74 2917R, 21P, 27P, 34P, 35E 8.2 16 19 30 14H, 17R, 21P, 27P, 35E 8.4 16 5931 14E, 17R, 21P, 27P, 31P 8.2 45 85 32 14E, 17R, 21P, 27P, 34P 8.2 4578 33 14E, 17R, 21P, 28P, 35E 5.9 9 0 34 17R, 21P, 27P, 35K 10.6 35 9935 17R, 21P, 27P, 35K 10.2 45 100 36 14E, 17R, 21P, 27P, 34K 9.9 45 10037 14E, 17R, 21P, 27P, 29P 8.2 15 98 38 17R, 21P, 27P, 35R 11.4 27 67 3917R, 21P, 27P, 34R 11.7 45 100 40 17R, 21P, 27P, 34H 10.1 26 92 41 17R,21P, 27P 8.8 7 4 42 17R, 21P, 27P 11.5 2 9 43 17R, 21P, 27P 11.5 4 9 44−1K, 1R, 17R, 21P, 27P, 35H 11.4 45 81 45 −1K, 1R, 17R, 21P, 27P, 35H11.4 45 87 46 −1G, 1R, 17R, 21P, 27P 11.4 24 0 47 −1G, 1R, 17R, 21P,27P, 35H 11.4 45 84 48 17R, 21P, 27P 8.8 25 1 49 17R, 21P, 27P, 31P 8.88 5 50 17R, 21P, 27P, 34P 8.8 2 8 51 14E, 17R, 21P, 27P, 35R 8.8 7 91 5214D, 17R, 21P, 27P, 35R 7.2 41 98 53 17R, 21P, 27P, 28P, 31P 8.8 18 0 5417R, 21P, 27P, 29P, 31P 8.8 15 0 55 17R, 21P, 27P, 28P, 34P 8.8 24 0 5617R, 21P, 27P, 29P, 34P 8.8 22 0 57 17R, 21P, 27P, 31P, 35H 8.8 45 86 5817R, 21P, 27P, 34P, 35H 8.8 38 86 59 14D, 17R, 21K, 27P, 35D 5.8 23 5 6017R, 21P, 27P, 35H 8.8 45 92 61 14H, 17R, 21P, 27P, 31P 8.8 45 92 6214H, 17R, 21P, 27P, 31P 8.8 45 92 63 14R, 17R, 21P, 27P, 31P 11.4 45 9264 14R, 17R, 21P, 27P, 31P 11.4 45 85 65 14R, 17R, 21P, 27P, 34P 11.4 4586 66 14H, 17R, 21P, 27P, 35H 8.8 45 88 67 14H, 17R, 21P, 27P, 34P 8.826 58 68 14H, 17R, 21P, 27P, 34P 8.8 24 73 69 14H, 17R, 21P, 27P 8.8 2213 70 14H, 17R, 21P, 27P 8.8 7 0 71 14G, 17R, 21P, 27P, 31P 8.8 11 0 7214A, 17R, 21P, 27P, 31P 8.8 13 0 73 14S, 17R, 21P, 27P, 31P 8.8 12 1 7414K, 17R, 21P, 27P, 31P 10.2 45 87 75 14T, 17R, 21P, 27P, 31P 8.8 25 1276 17R, 21P, 27P, 34H 8.8 22 31 77 17R, 21P, 27P, 34H 8.8 21 64 78 17R,21P, 27P, 34R 11.4 13 15 79 17R, 21P, 27P, 34R 11.4 21 81 80 14H, 17R,21P, 27P, 34H 8.8 28 90 81 14H, 17R, 21P, 27P, 34H 8.8 45 93 82 14R,17R, 21P, 27P 11.4 12 63 83 14R, 17R, 21P, 27P 11.4 12 79 84 14H, 17R,21P, 27P, 34R 11.4 45 100 85 14H, 17R, 21P, 27P, 34R 11.4 45 100 86 17R,21P, 27P, 34H 7.4 32 60 87 14E, 17R, 21P, 27P, 34H 6.6 45 74 88 14E,17R, 21P, 27P, 34R 7.2 45 100 89 14E, 17R, 21P, 27P, 35R 7.2 43 86 9014H, 17R, 21P, 27P 11.5 10 42 91 17R, 21P, 27P, 34H 11.5 4 88 92 14H,17R, 21P, 27P 7.4 8 0 93 14A, 17R, 21P, 27P, 34H 8.8 16 89 94 14A, 17R,21P, 27P, 34P 8.8 10 0 95 17R, 21P, 27P, 34R 11.4 37 76 96 17R, 21P,27P, 31P 8.8 12 32 97 17R, 21P, 27P, 34H 8.8 30 77 98 17R, 21P, 27P, 34P8.8 4 0 99 −1G, 1R, 14H, 17R, 21P, 27P 11.4 17 29 100 −1G, 1R, 14H, 17R,21P, 27P, 34H 11.4 33 77 101 −1G, 1R, 14A, 17R, 21P, 27P, 34H 11.4 45 85102 −1G, 1R, 14H, 17R, 21P, 27P, 34P 11.4 26 77 103 −1G, 1R, 14A, 17R,21P, 27P, 34P 11.4 45 82 104 14E, 17R, 21P, 27P, 34H, 35E 5.7 45 97 10514E, 17R, 21P, 27P, 34R, 35E 5.9 45 90 106 14E, 17R, 21P, 27P, 34P, 35E4.9 33 56 107 14E, 17R, 21P, 27P, 34H, 35E 6.6 45 88 108 14E, 17R, 21P,27P, 34R, 35E 7.2 45 87 109 14E, 17R, 21P, 27P, 34P, 35E 5.9 35 43 11014E, 17R, 21P, 27P, 34P, 35R 7.2 17 3 111 17R, 21P, 27P, 34H 8.8 10 79112 17R, 21P, 27P, 34H 8.8 30 86 113 17R, 21P, 27P, 34H 8.8 45 89 11414E, 17R, 21P, 27P, 34P, 37P 7.2 45 100 115 14H, 17R, 21P, 27P, 34P, 37P10.4 45 100 116 14H, 17R, 21P, 27P, 31P, 34P 8.8 45 88 117 14E, 17R,21P, 27P, 34P, 35R 8.8 45 78 118 14E, 17R, 21P, 27P, 34P, 35H 7.4 45 100119 17R, 21P, 27P, 31P, 34P, 35R 8.2 10 93 120 14S, 17R, 21P, 27P, 34P,35E 5.8 14 1 121 14E, 17R, 21P, 31P, 34P, 35E 4.9 3 0 122 14D, 17R, 21P,27P, 34P, 35E 4.8 45 100 123 14D, 17R, 21P, 27P, 34P, 35E 5.9 30 11 12414E, 17R, 21P, 27P, 34P, 35H 6.6 45 90 125 14E, 17R, 21P, 27P, 34P, 35E,37P 4.9 23 24 126 14E, 17R, 23P, 34P, 35E 4.9 0 0 127 14E, 17R, 21P,27P, 34P, 37F 5.8 25 0 128 14E, 17R, 21P, 27P, 35H 7.4 41 100 129 14D,17R, 21P, 27P, 34P, 35R 8.8 45 100 130 14D, 17R, 21P, 27P, 34P, 35R 7.245 98 131 14d, 17R, 21P, 27P, 35R 7.2 132 14D, 17R, 21P, 27P, 35R 13.0

Food Intake

The polypeptides were tested with respect to their effect in the FoodIntake assay (Assay (I)) and the results shown in Table 11.

The compounds disclosed in Table 11 have a hAmylinR IC50 value of lessthan 1200 pM. Details of the albumin binding moiety, linker andacylation sites have been removed from these Tables. For full structuralinformation please consult the entry with a corresponding compoundnumber in Table 2. Further details regarding the compounds, such asIUPAC nomenclature may be found in Table 14.

TABLE 11 Food intake Food intake reduction reduction Food intake Foodintake 0-24 h 24-48 h reduction reduction 30 nmol/kg 30 nmol/kg 0-24 h24-48 h Example # (%) (%) 3 nmol/kg (%) 3 nmol/kg (%) 2 72 62 39 10 2422 1 28 49 38 30 41 17 32 62 7 34 37 25 35 51 15 38 47 0 39 36 8 40 5126 45 27 3 47 51 0 51 52 30 52 63 50 25 15 57 62 16 60 69 21 61 53 18 6262 18 64 4 3 65 10 0 67 47 0 68 33 0 76 31 2 77 40 16 80 46 9 81 40 3 8410 0 85 30 6 86 48 26 87 29 20 88 31 15 89 46 37 95 22 0 104 31 28 10663 69 108 29 0 109 89 91 57 50 110 68 31 111 17 0 113 48 2 117 61 4 11877 30 43 1 120 66 61 122 50 50 124 73 38 130 80 27 131 17 14

Pharmacokinetic Profile (PK)

PK miniping i.v. T½ (hours)

The half life of the polypeptides of the present invention were testedin mini pigs as described in Assay (IX) and the data are given in Table12.

The compounds disclosed in Table 13 have a hAmylinR IC50 value of lessthan 1200 pM. Details of the albumin binding moiety, linker andacylation sites have been removed from these Tables. For full structuralinformation please consult the entry with a corresponding compoundnumber in Table 2. Further details regarding the compounds, such as UPACnomenclature may be found in Table 14.

TABLE 12 Example # PK minipig i.v. T½ (hours) 52 99.5 76 76 77 81 85 8586 103.9 106 49 109 95PK rat i.v. T½ (hours)

The half life of the polypeptides of the present invention were testedin rats as described in Assay (X) and the data are given in Table 13.

The compounds disclosed in Table 13 have a hAmylinR IC50 value of lessthan 1200 pM. Details of the albumin binding moiety, linker andacylation sites have been removed from these Tables. For full structuralinformation please consult the entry with a corresponding compoundnumber in Table 2. Further details regarding the compounds, such asIUPAC nomenclature may be found in Table 14.

TABLE 13 Example # PK rat i.v. T½ (hours) 65 3 67 7 110 14 109 17 77 1886 20 52 21 89 23 2 28 106 37

Compounds

Some of the preferred compounds of the present invention are presentedin Table 14.

TABLE 14 Compound (Example) No. IUPAC Nomenclature 1N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Asp14,Arg17,Pro21,Pro26,Asp35]-h-amylin 2N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Asp14,Arg17,Pro21,Pro27,Asp35]-h-amylin 3N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Asp14,Arg17,Pro22,Pro26,Asp35]-h-amylin 4N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro25,Pro28,Pro29,Pro37]-h-amylin 5N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro26,Pro37]-h-amylin 6N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro25,Pro28,Pro29]-h-amylin 7N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro26]-h-amylin 8N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro37]-h-amylin 9N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27]-h-amylin 10N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Asp14,Arg17,Pro21,Pro27,Pro37]-h-amylin 11N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,Asp35,Pro37]-h-amylin 12N^(ε1)-[(4S)--4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro37]-h-amylin 13N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro37]-h-amylin 14N^(α1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro37]-h-amylin 15 N^(α1)N^(α1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Glu14,Arg17,Pro21,Pro27]-h-amylin 16N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,Arg35]-h-amylin 17N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,His34]-h-amylin 18N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,His35]-h-amylin 19N^(α1)-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Glu14,Arg17,Pro21,Pro27]-h-amylin 20N^(α1)-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Glu14,Arg17,Pro21,Pro27,Pro37]-h-amylin 21N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg17,Pro21,Pro27]-h-amylin 22N^(α1)N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,Glu35]-h-amylin 23N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg17,Pro21,Pro27,Glu35]-h-amylin 24N^(α1)-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27]-h-amylin 25N^(ε1)-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,Glu35]-h-amylin 26N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,Glu35]-h-amylin 27N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg17,Pro21,Pro27,Glu35]-h-amylin 28N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg17,Pro21,Pro27,Pro31,Glu35]-h-amylin 29N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg17,Pro21,Pro27,Pro34,Glu35]-h-amylin 30N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[His14,Arg17,Pro21,Pro27,Glu35]-h-amylin 31N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro31]-h-amylin 32N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro34]-h-amylin 33N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro28,Glu35]-h-amylin 34N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg17,Pro21,Pro27,Lys35]-h-amylin 35N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg17,Pro21,Pro27,Lys35]-h-amylin 36N{Alpha-1}-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,Lys34]-h-amylin 37N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro29]-h-amylin 38N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,Arg35]-h-amylin 39N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg17,Pro21,Pro27,Arg34]-h-amylin 40N^(α1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg17,Pro21,Pro27,His34]-h-amylin 41N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27]-h-amylin 42N^(ε1)-19-carboxynonadecanoyl-[Arg17,Pro21,Pro27]-h-amylin 43N^(ε1)-[2-[2-[2-(19-carboxynonadecanoylamino)ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27]-h-amylin 44 N^(ε)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]Lys[Arg1,Arg17,Pro21,Pro27,His35]-h-amylin 45 N^(ε)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]Lys[Arg1,Arg17,Pro21,Pro27,His35]-h-amylin 46N⁻¹-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-Gly[Arg1,Arg17,Pro21,Pro27]-h-amylin 47N⁻¹-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-Gly[Arg1,Arg17,Pro21,Pro27,His35]-h-amylin 48N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg17,Pro21,Pro27]-h-amylin 49 N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,Pro31]-h-amylin 50N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,Pro34]-h-amylin 51N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,Arg35]-h-amylin 52N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Asp14,Arg17,Pro21,Pro27,Arg35]-h-amylin 53N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,Pro28,Pro31]-h-amylin 54N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,Pro29,Pro31]-h-amylin 55N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,Pro28,Pro34]-h-amylin 56N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,Pro29,Pro34]-h-amylin 57N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,Pro31,His35]-h-amylin 58N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,Pro34,His35]-h-amylin 59N^(ε21)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Asp14,Arg17,Lys21,Pro27,Asp35]-h-amylin 60N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg17,Pro21,Pro27,His35]-h-amylin 61N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[His14,Arg17,Pro21,Pro27,Pro31]-h-amylin 62N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[His14,Arg17,Pro21,Pro27,Pro31]-h-amylin 63N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg14,Arg17,Pro21,Pro27,Pro31]-h-amylin 64N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Arg14,Arg17,Pro21,Pro27,Pro31]-h-amylin 65N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg14,Arg17,Pro21,Pro27,Pro34]-h-amylin 66N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[His14,Arg17,Pro21,Pro27,His35]-h-amylin 67N^(ε1)N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[His14,Arg17,Pro21,Pro27,Pro34]-h-amylin 68N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[His14,Arg17,Pro21,Pro27,Pro34]-h-amylin 69N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[His14,Arg17,Pro21,Pro27]-h-amylin 70N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[His14,Arg17,Pro21,Pro27]-h-amylin 71N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Gly14,Arg17,Pro21,Pro27,Pro31]-h-amylin 72N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Ala14,Arg17,Pro21,Pro27,Pro31]-h-amylin 73N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Ser14,Arg17,Pro21,Pro27,Pro31]-h-amylin 74N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Lys14,Arg17,Pro21,Pro27,Pro31]-h-amylin 75N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Thr14,Arg17,Pro21,Pro27,Pro31]-h-amylin 76N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,His34]-h-amylin 77N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg17,Pro21,Pro27,His34]-h-amylin 78N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,Arg34]-h-amylin 79N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg17,Pro21,Pro27,Arg34]-h-amylin 80N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[His14,Arg17,Pro21,Pro27,His34]-h-amylin 81N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[His14,Arg17,Pro21,Pro27,His34]-h-amylin 82N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[Arg14,Arg17,Pro21,Pro27]-h-amylin 83N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Arg14,Arg17,Pro21,Pro27]-h-amylin 84N^(ε1)-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[His14,Arg17,Pro21,Pro27,Arg34]-h-amylin 85N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[His14,Arg17,Pro21,Pro27,Arg34]-h-amylin 86N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Arg17,Pro21,Pro27,His34]-h-amylin 87N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Glu14,Arg17,Pro21,Pro27,His34]-h-amylin 88N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Glu14,Arg17,Pro21,Pro27,Arg34]-h-amylin 89N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Glu14,Arg17,Pro21,Pro27,Arg35]-h-amylin 90N^(ε1)-[2-[2-[2-(19-carboxynonadecanoylamino)ethoxy]ethoxy]acetyl]-[His14,Arg17,Pro21,Pro27]-h-amylin 91N^(ε1)-[2-[2-[2-(19-carboxynonadecanoylamino)ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,His34]-h-amylin 92N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[His14,Arg17,Pro21,Pro27]-h-amylin 93N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Ala14,Arg17,Pro21,Pro27,His34]-h-amylin 94N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Ala14,Arg17,Pro21,Pro27,Pro34]-h-amylin 95N^(ε1)-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,Arg34]-h-amylin 96N^(ε1)-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,Pro31]-h-amylin 97N^(ε1)-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,His34]-h-amylin 98N^(ε1)-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Arg17,Pro21,Pro27,Pro34]-h-amylin 99N{-1}-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-Gly[Arg1,His14,Arg17,Pro21,Pro27]-h-amylin 100N⁻¹-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-Gly[Arg1,His14,Arg17,Pro21,Pro27,His34]-h-amylin 101N⁻¹-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-Gly[Arg1,Ala14,Arg17,Pro21,Pro27,His34]-h-amylin 102N⁻¹-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-Gly[Arg1,His14,Arg17,Pro21,Pro27,Pro34]-h-amylin 103N⁻¹-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-Gly[Arg1,Ala14,Arg17,Pro21,Pro27,Pro34]-h-amylin 104N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Glu14,Arg17,Pro21,Pro27,His34,Glu35]-h-amylin 105N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Glu14,Arg17,Pro21,Pro27,Arg34,Glu35]-h-amylin 106N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro34,Glu35]-h-amylin 107N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,His34,Glu35]-h-amylin 108N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,Arg34,Glu35]-h-amylin 109N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro34,Glu35]-h-amylin 110N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro34,Arg35]-h-amylin 111N^(ε1)-[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butanoyl]-[Arg17,Pro21,Pro27,His34]-h-amylin 112N^(ε1)-[(4S)-4-carboxy-4-(13-carboxytridecanoylamino)butanoyl]-[Arg17,Pro21,Pro27,His34]-h-amylin 113N^(ε1)-[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]-[Arg17,Pro21,Pro27,His34]-h-amylin 114N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro34,Pro37]-h-amylin 115N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[His14,Arg17,Pro21,Pro27,Pro34,Pro37]-h-amylin 116N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[His14,Arg17,Pro21,Pro27,Pro31,Pro34]-h-amylin 117N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro34,Arg35]-h-amylin 118N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro34,His35]-h-amylin 119N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Arg17,Pro21,Pro27,Pro31,Pro34,Arg35]-h-amylin 120N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Ser14,Arg17,Pro21,Pro27,Pro34,Glu35]-h-amylin 121N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Glu14,Arg17,Pro21,Pro31,Pro34,Glu35]-h-amylin 122N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Asp14,Arg17,Pro21,Pro27,Pro34,Glu35]-h-amylin 123N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Asp14,Arg17,Pro21,Pro27,Pro34,Glu35]-h-amylin 124N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro34,His35]-h-amylin 125N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro34,Glu35,Pro37]-h-amylin 126N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Glu14,Arg17,Pro23,Pro34,Glu35]-h-amylin 127N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Glu14,Arg17,Pro21,Pro27,Pro34,Phe37]-h-amylin 128N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Glu14,Arg17,Pro21,Pro27,His35]-h-amylin 129N^(ε1)-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-[Asp14,Arg17,Pro21,Pro27,Pro34,Arg35]-h-amylin 130N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Asp14,Arg17,Pro21,Pro27,Pro34,Arg35]-h-amylin 131N^(ε1)-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[D-Asp14,Arg17,Pro21,Pro27,Arg35]-h-amylin 132[Asp14,Arg17,Pro21,Pro27,Arg35]-h-amylin

TABLE 15 Plasma Compond Food intake Food intake red calcium red(Example) Dose red (%)* (%)* (%)** No (nmol/kg) 0-24 h 24-48 h 0-12 hPramlintide 1000 25 0 28 Salmon 3 nt nt 35 calcitonin Salmon 30 87 19 39calcitonin  2 3 39 10 nt  2 30 72 62 nt  2 100 nt nt 9  51 30 52 30 10 52 3 25 15 nt  52 30 63 50 12  86 30 48 26 0  89 30 46 37 7 106 30 6369 6 109 3 57 50 7 109 30 89 91 27 110 30 68 31 8 117 30 61 4 9 118 3 431 nt 118 30 77 30 26 124 10 nt nt 3 124 30 73 38 11 *Reduction of foodintake in rats after single s.c. administration compared to vehicletreated rats **Maximal plasma calcium reduction in rats after singles.c. administration compared to vehicle treated rats nt: not tested

Observations

Without wishing to be bound by theory, for some of the preferredembodiments of the present invention, a substitution at amino acidresidue 17 and preferably also a substitution at amino acid residue 27and/or a substitution at amino acid residue 35 can provide an increasedpotency for the polypeptides of the present invention. Othersubstitutions can provide further improvements in potency for thepolypeptides of the present invention.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference in theirentirety and to the same extent as if each reference were individuallyand specifically indicated to be incorporated by reference and were setforth in its entirety herein (to the maximum extent permitted by law).

All headings and sub-headings are used herein for convenience only andshould not be construed as limiting the invention in any way.

The use of any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

The citation and incorporation of patent documents herein is done forconvenience only and does not reflect any view of the validity,patentability, and/or enforceability of such patent documents.

This invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw.

SEQUENCE LISTING SEQ ID NO: 1Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser-Asn-Asn-Phe-Gly-Ala-Ile-Leu-Ser-Ser-Thr-Asn-Val-Gly-Ser-Asn-Thr- Tyr SEQ ID NO: 2Ala-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asp-Phe-Leu-Arg-His-Ser-Ser-Pro-Asn-Phe-Gly-Pro-Pro-Pro-Pro-Pro-Thr-Pro-Val-Gly-Pro-Asp-Thr- Pro SEQ ID NO: 3Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asp-Phe-Leu-Arg-His-Ser-Ser-Pro-Asn-Phe-Gly-Ala-Ile-Pro-Ser-Ser-Thr-Asn-Val-Gly-Ser-Asn-Thr- Tyr SEQ ID NO: 4Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asp-Phe-Leu-Arg-His-Ser-Ser-Pro-Asn-Phe-Gly-Ala-Ile-Pro-Ser-Ser-Thr-Asn-Val-Gly-Ser-Arg-Thr- Tyr SEQ ID NO: 5Xaa₁-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Xaa₁₄-Phe-Leu-Xaa₁₇-His-Ser-Ser-Xaa₂₁-Asn-Phe-Gly-Xaa₂₅-Xaa₂₆-Xaa₂₇-Xaa₂₈-Xaa₂₉-Thr-Xaa₃₁-Val-Gly-Xaa₃₄-Xaa₃₅-Thr-Xaa₃₇whereinXaa₁ is independently selected from Ala, Cys, Glu, Gly, His, Arg, Serand Lys;Xaa₁₄ is independently selected from Asp, Glu, His, Asn, Arg, Gly, Ala,Ser, Lys, Thr and Cys;Xaa₁₇ is independently selected from Arg and Val;

Xaa₂₁ is Pro;

Xaa₂₅ is independently selected from Pro and Ala;Xaa₂₆ is independently selected from Pro and Ile;Xaa₂₇ is independently selected from Pro and Leu;Xaa₂₈ is independently selected from Pro and Ser;Xaa₂₉ is independently selected from Pro and Ser;Xaa₃₁ is independently selected from Pro and Asn;Xaa₃₄ is independently selected from Pro, His, Lys, Arg and SerXaa₃₅ is independently selected from Asp, Arg, Glu, Lys, His and Asn;Xaa₃₇ is independently selected from Pro and Tyr;and where the C-terminal may optionally be derivatized.

1. A polypeptide which is an analogue of SEQ ID No: 1 having about a10-fold or greater selectivity for binding to the human amylin receptorover binding to the human calcitonin receptor and wherein: (a) saidanalogue of SEQ ID No: 1 comprises a proline residue at position 21;wherein the amino acid sequence numbering of the analogue corresponds tothe amino acid numbering sequence of SEQ ID No: 1; and (b) wherein thepolypeptide has at least one substituent attached to at least one of itsamino acid residues.
 2. The polypeptide according to claim 1 wherein thepolypeptide has an IC₅₀ in a human amylin receptor binding assay ofabout 1200 pM or less.
 3. The polypeptide according to claim 1 whereinthe analogue comprises a proline or leucine residue at position
 27. 4.The polypeptide according to claim 1 wherein the analogue comprises aproline residue at position
 27. 5. The polypeptide according to claim 1wherein the analogue comprises an amino acid residue at position 14which is aspartic acid, an amino acid residue at position 17 which isarginine, an amino acid residue at position 21 which is proline, anamino acid residue at position 27 which is proline and an amino acidresidue at position 35 which is arginine.
 6. The polypeptide accordingto claim 1 comprising an analogue of SEQ ID No: 1 according to formula(I): (I) Xaa₁-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Xaa₁₄-Phe-Leu-Xaa₁₇-His-Ser-Ser-Xaa₂₁-Asn-Phe-Gly-Xaa₂₅-Xaa₂₆-Xaa₂₇-Xaa₂₈-Xaa₂₉-Thr-Xaa₃₁-Val-Gly-Xaa₃₄-Xaa₃₅-Thr-Xaa₃₇;

wherein Xaa₁ is independently selected from Ala, Cys, Glu, Gly, His,Arg, Ser and Lys; Xaa₁₄ is independently selected from Asp, Glu, His,Asn, Arg, Gly, Ala, Ser, Lys, Thr and Cys; Xaa₁₇ is independentlyselected from Arg and Val; Xaa₂₁ is Pro; Xaa₂₅ is independently selectedfrom Pro and Ala; Xaa₂₆ is independently selected from Pro and Ile;Xaa₂₇ is independently selected from Pro and Leu; Xaa₂₈ is independentlyselected from Pro and Ser; Xaa₂₉ is independently selected from Pro andSer; Xaa₃₁ is independently selected from Pro and Asn; Xaa₃₄ isindependently selected from Pro, His, Lys, Arg and Ser Xaa₃₅ isindependently selected from Asp, Arg, Glu, Lys, His and Asn; Xaa₃₇ isindependently selected from Pro and Tyr; and where the C-terminal mayoptionally be derivatized.
 7. The polypeptide according to claim 6wherein Xaa₁ is Lys, Xaa₁₄ is Asp, Xaa₁₇ is Arg, Xaa₂₁ is Pro, Xaa₂₅ isAla, Xaa₂₆ is Ile, Xaa₂₇ is Pro, Xaa₂₈ is Ser, Xaa₂₉ is Ser, Xaa₃₁ isAsn, Xaa₃₄ is Ser, Xaa₃₅ is Asn, Xaa₃₇ is Tyr.
 8. The polypeptideaccording to claim 1 wherein the substituent group is selected from thegroup consisting of C20diacid, C20diacid-γGlu, C20diacid-γGlu-γGlu,C20diacid-γGlu-γGlu-γGlu, C20diacid-OEG, C20diacid-γGlu-OEG,C20diacid-γGlu-OEG-OEG, C18diacid-γGlu, C16diacid-γGlu, andC14diacid-γGlu.
 9. The polypeptide according to claim 1 wherein asubstituent is attached to the α-amino group of the N-terminal aminoacid residue or to a Lys residue or cysteine residue only.
 10. Thepolypeptide according to claim 1, selected from the group consisting ofany of the polypeptides presented in Table
 2. 11. The polypeptideaccording to claim 1, selected from the group consisting of any of thepolypeptides presented in Table
 3. 12. The polypeptide according toclaim 1 wherein the polypeptide isN-ε-1-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxynonadecanoylamino)butyrylamino]butyryl}-[Asp14,Arg17,Pro21,Pro27,Arg35]-human amylin.
 13. A method of treating orpreventing hyperglycemia, type 2 diabetes, impaired glucose tolerance,type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia,cognitive disorders, atherosclerosis, myocardial infarction, coronaryheart disease and other cardiovascular disorders, stroke, inflammatorybowel syndrome, dyspepsia and gastric ulcers and/or for use indecreasing food intake, decreasing β-cell apoptosis, increasing β-cellfunction and β-cell mass, and/or for restoring glucose sensitivity toβ-cells, comprising administering the polypeptide of claim 1 to a patentin need thereof.
 14. A pharmaceutical composition comprising thepolypeptide of claim 1 and a pharmaceutically acceptable excipient. 15.A process for preparing a pharmaceutical composition comprising mixingthe polypeptide of claim 1 with a pharmaceutically acceptable excipient.